Quinazoline derivatives

ABSTRACT

The invention concerns quinazoline derivatives of the formula I                    
     wherein X 1  is a direct link or a group such as CO, C(R 2 ) 2  and CH(OR 2 ); 
     wherein Q 1  is phenyl, naphthyl or a 5- or 6-membered heteroaryl moiety and Q 1  optionally bears up to 3 substituents; 
     wherein m is 1 or 2 and each R 1  may be a group such as hydrogen, halogeno and trifluoromethyl; and 
     wherein Q 2  may be phenyl or a 9- or 10-membered bicyclic heterocyclic moiety and Q 2  optionally bears up to 3 substituents; 
     or a pharmaceutically-acceptable salt thereof; 
     processes for their preparation, pharmaceutical compositions containing them and the use of their receptor tyrosine kinase inhibitory properties in the treatment of proliferative disease such as cancer.

This appln is a Divisional of Ser. No. 08/796,483 filed Feb. 13, 1997.

The invention relates to quinazoline derivatives, orpharmaceutically-acceptable salts thereof, which possessanti-proliferative activity such as anti-cancer activity and areaccordingly useful in methods of treatment of the human or animal body.The invention also relates to processes for the manufacture of saidquinazoline derivatives, to pharmaceutical compositions containing themand to their use in the manufacture of medicaments for use in theproduction of an anti-proliferative effect in a warm-blooded animal suchas man.

Many of the current treatment regimes for cell proliferation diseasessuch as psoriasis and cancer utilise compounds which inhibit DNAsynthesis. Such compounds are toxic to cells generally but their toxiceffect on rapidly dividing cells such as tumour cells can be beneficial.Alternative approaches to anti-proliferative agents which act bymechanisms other than the inhibition of DNA synthesis have the potentialto display enhanced selectivity of action.

In recent years it has been discovered that a cell may become cancerousby virtue of the transformation of a portion of its DNA into an oncogenei.e. a gene which, on activation, leads to the formation of malignanttumour cells (Bradshaw, Mutagenesis, 1986, 1, 91). Several suchoncogenes give rise to the production of peptides which are receptorsfor growth factors. The growth factor receptor complex subsequentlyleads to an increase in cell proliferation. It is known, for example,that several oncogenes encode tyrosine kinase enzymes and that certaingrowth factor receptors are also tyrosine kinase enzymes (Yarden et al.,Ann. Rev. Biochem., 1988, 57, 443; Larsen et al. Ann. Reports in Med.Chem. 1989, Chpt. 13).

Receptor tyrosine kinases are important in the transmission ofbiochemical signals which initiate cell replication. They are largeenzymes which span the cell membrane and possess an extracellularbinding domain for growth factors such as epidermal growth factor (EGF)and an intracellular portion which functions as a kinase tophosphorylate tyrosine amino acids in proteins and hence to influencecell proliferation. Various classes of receptor tyrosine kinases areknown (Wilks, Advances in Cancer Research, 1993, 60, 43-73) based onfamilies of growth factors which bind to different receptor tyrosinekinases. The classification includes Class I receptor tyrosine kinasescomprising the EGF family of receptor tyrosine kinases such as the EGF,transforming growth factor a (TGFα), NEU, erbB, Xmrk, DER and let23receptors, Class II receptor tyrosine kinases comprising the insulinfamily of receptor tyrosine kinases such as the insulin. IGFI andinsulin-related receptor (IRR) receptors and Class III receptor tyrosinekinases comprising the plateletderived growth factor (PDGF) family ofreceptor tyrosine kinases such as the PDGFα, PDGFβ andcolony-stimulating factor 1 (CSF1) receptors. It is known that Class Ikinases such as the EGF family of receptor tyrosine kinases arefrequently present in common human cancers such as breast cancer(Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al.,Oncogene Res., 1988, 3, 21 and Klijn et al., Breast Cancer Res. Treat.,1994, 29, 73), non-small cell lung cancers (NSCLCs) includingadenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi etal., Int. J. Cancer, 1990, 45, 269 and Rusch et al., Cancer Research,1993, 53, 2379) and squamous cell cancer of the lung (Hendler et al.,Cancer Cells, 1989, 7, 347), bladder cancer (Neal et al., Lancet, 1985,366), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142),gastrointestinal cancer such as colon, rectal or stomach cancer (Bolenet al., Oncogene Res., 1987, 1, 149), cancer of the prostate (Visakorpiet al., Histochem. J., 1992, 24, 481), leukaemia (Konaka et al., Cell,1984, 31, 1035) and ovarian, bronchial or pancreatic cancer (EuropeanPatent Specification No. 0400586). As further human tumour tissues aretested for the EGF family of receptor tyrosine kinases it is expectedthat its widespread prevalance will be established in further cancerssuch as thyroid and uterine cancer. It is also known that EGF typetyrosine kinase activity is rarely detected in normal cells whereas itis more frequently detectable in malignant cells (Hunter, Cell, 1987,50, 823). It has been shown more recently (W J Gullick, Brit. Med.Bull., 1991, 47, 87) that EGF receptors which possesses tyrosine kinaseactivity are overexpressed in many human cancers such as brain, lungsquamous cell, bladder, gastric, colorectal, breast, head and neck,oesophageal, gynaecological and thyroid tumours.

Accordingly it has been recognised that an inhibitor of receptortyrosine kinases should be of value as a selective inhibitor of thegrowth of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933).Support for this view is provided by the demonstration that erbstatin,an EGF receptor tyrosine kinase inhibitor, specifically attenuates thegrowth in athymic nude mice of a transplanted human mammary carcinomawhich expresses EGF receptor tyrosine kinase but is without effect onthe growth of another carcinoma which does not express EGF receptortyrosine kinase (Toi et al., Eur. J. Cancer Clin. Oncol., 1990, 26,722). Various derivatives of styrene are also stated to possess tyrosinekinase inhibitory properties (European Patent Application Nos. 0211363,0304493 and 0322738) and to be of use as anti-tumour agents. The in vivoinhibitory effect of two such styrene derivatives which are EGF receptortyrosine kinase inhibitors has been demonstrated against the growth ofhuman squamous cell carcinoma inoculated into nude mice (Yoneda et al.,Cancer Research, 1991, 51, 4430). Accordingly it has been indicated thatClass I receptor tyrosine kinase inhibitors will prove to be useful inthe treatment of a variety of human cancers. Various known tyrosinekinase inhibitors are disclosed in a more recent review by T R Burke Jr.(Drugs of the Future, 1992, 17, 119).

EGF type receptor tyrosine kinases have also been implicated innon-malignant proliferative disorders such as psoriasis (Elder et al.,Science, 1989, 243, 811). It is therefore expected that inhibitors ofEGF type receptor tyrosine kinases will be useful in the treatment ofnon-malignant diseases of excessive cellular proliferation such aspsoriasis (where TGFα is believed to be the most important growthfactor) and benign prostatic hypertrophy (BPH), atherosclerosis andrestenosis.

It is known from European Patent Applications Nos. 0520722 and 0566226and from International Patent Applications WO 95/15758, WO 95/19169, WO96/09294, WO 96/15118, WO 96/16960 and WO 96/30347 that certainquinazoline derivatives which bear an anilino substituent at the4-position possess receptor tyrosine kinase inhibitory activity. It isfurther known from European Patent Application No. 0602851 and fromInternational Patent Application WO 95/23141 that certain quinazolinederivatives which bear an anilino substituent at the 4-position alsopossess receptor tyrosine kinase inhibitory activity.

It is further known from International Patent Application WO 92/20642that certain aryl and heteroaryl compounds inhibit EGF and/or PDGFreceptor tyrosine kinase. There is the disclosure of certain quinazolinederivatives therein but no mention is made of 4-anilinoquinazolinederivatives.

It is further known from European Patent Application No. 0635507 andfrom International Patent Applications WO 95/06648, WO 95/19970 and WO96/29331 that certain tricyclic compounds which comprise a 5- or6-membered ring fused to the benzo-ring of a quinazoline possessreceptor tyrosine kinase inhibitory activity or phosphodiesteraseinhibitory activity. It is also known from European Patent ApplicationNo. 0635498 that certain quinazoline derivatives which carry an aminogroup at the 6-position and a halogeno group at the 7-position possessreceptor tyrosine kinase inhibitory activity.

The in vitro anti-proliferative effect of a 4-anilinoquinazolinederivative has been disclosed by Fry et al., Science, 1994, 265, 1093.It was stated that the compound4-(3-bromoanilino)-6,7-dimethoxyquinazoline was a highly potentinhibitor of EGF receptor tyrosine kinase.

The in vivo inhibitory effect of a 4,5-dianilinophthalimide derivativewhich is an inhibitor of the EGF family of receptor tyrosine kinases hasbeen demonstrated against the growth in BALB/c nude mice of a humanepidermoid carcinoma A-431 or of a human ovarian carcinoma SKOV-3(Buchdunger et al., Proc. Nat. Acad. Sci., 1994, 91, 2334).

It is further disclosed in International Patent Applications WO96/33977, WO 96/33978, WO 96/33979, WO 96/33980 and WO 96/33981 thatcertain further quinazoline derivatives which bear an anilinosubstituent at the 4-position possess receptor tyrosine kinaseinhibitory activity.

There is no disclosure in these documents of quinazoline derivativeswhich bear a heteroaryl moiety attached directly to the 6-position(other than the disclosure in International Patent Application WO96/16960 of certain 4-anilinoquinazolines which bear a 5- or 9-memberednitrogen-linked heteroaryl moiety at the 6-position) or attached to the6-position by way of a 1- or 2-atom chain, or of an aryl moiety attacheddirectly to the 6-position or attached to the 6-position by way of a 1-or 2-atom chain [other than the disclosure in European PatentApplication No. 0566226 of certain 4-anilinoquinazolines which bear anaryl moiety attached to the 6-position by way of a CONH, NHCH₂, CH₂NH orSCH₂ linking chain (with the aryl moiety attached to the first atom ofthese 2 atom linking groups, for example the carbon atom within the CONHgroup)].

We have now found that such compounds possess anti-proliferativeproperties which are believed to arise from their Class I (EGF type)receptor tyrosine kinase inhibitory activity.

According to the invention there is provided a quinazoline derivative ofthe formula I

wherein X¹ is a direct link or a group of the formula CO, C(R²)₂,CH(OR²), C(R²)₂—C(R²)₂, C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²),CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂,C(R²)₂O, C(R²)₂S or C(R²)₂N(R²), and each R² is independently hydrogenor (1-4C)alkyl;

wherein Q¹ is phenyl, naphthyl or a 5- or 6-membered heteroaryl moietycontaining up to 3 heteroatoms selected from oxygen, nitrogen andsulphur, which heterocyclic moiety is a single ring or is fused to abenzo ring, and Q¹ optionally bears up to 3 substituents selected fromhalogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano,nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy,pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy,morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy,(1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy,halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino,(1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino,(1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

wherein m is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl;

and wherein Q² is phenyl or a 9- or 10-membered bicyclic heterocyclicmoiety containing 1 or 2 nitrogen heteroatoms and optionally containinga further heteroatom selected from oxygen, nitrogen and sulphur, and Q²optionally bears up to 3 substituents selected from halogeno,trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy, carbamoyl,(1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, or Q² is a group of the formula II

wherein X² is a group of the formula CO, C(R³)₂, CH(OR³), C(R³)₂—C(R³)₂,C(R³)═C(R³), C≡C, CH(CN), O, S, SO, SO₂, N(R³), CON(R³), SO₂N(R³),N(R³)CO, N(R³)SO₂, OC(R³)₂, SC(R³)₂, C(R³)₂O or C(R³)₂S wherein each R³is independently hydrogen or (1-4C)alkyl, Q³ is phenyl or naphthyl or a5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heteroaryl moiety is asingle ring or is fused to a benzo ring, and wherein said phenyl ornaphthyl group or heteroaryl moiety optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-[(1-4C)alkyl]carbamoyl, n is 1, 2 or 3 and each R⁴ isindependently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino or (2-4C)alkanoylamino;

or a pharmaceutically-acceptable salt thereof;

provided that, when Q¹ is optionally-substituted phenyl, X¹ is notN(R²)CO, N(R²)SO₂, OC(R²)₂, N(R²)C(R²)₂, C(R²)₂S or C(R²)₂N(R²); andwhen X¹ is a direct link, Q¹ is not a 5- or 9-membered nitrogen-linkedheteroaryl moiety containing up to 3 nitrogen heteroatoms.

According to a further aspect of the invention there is provided aquinazoline derivative of the formula I

wherein X¹ is a direct link or a group of the formula CO, C(R²)₂,CH(OR²), C(R²)₂—C(R²)₂, C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²),CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂,C(R²)₂O, C(R²)₂S or C(R²)₂N(R²), and each R² is independently hydrogenor (1-4C)alkyl;

wherein Q¹ is a 5- or 6-membered heteroaryl moiety containing up to 3heteroatoms selected from oxygen, nitrogen and sulphur, whichheterocyclic moiety is a single ring or is fused to a benzo ring, and Q¹optionally bears up to 3 substituents selected from halogeno, hydroxy,amino, trifluoromethoxy, trifluoromethyl cyano, nitro, carboxy,carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy.(2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy,pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy,morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy,(1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy,halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino,(1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino,(1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl -(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;

wherein m is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl;

and wherein Q² is phenyl which optionally bears up to 3 substituentsselected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;

or a pharmaceutically-acceptable salt thereof; provided that, when X¹ isa direct link, Q¹ is not a 5- or 9-membered nitrogen-linked heteroarylmoiety containing up to 3 nitrogen heteroatoms.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample when R¹ is a hydroxy-(2-4C)alkoxy group, suitable values forthis generic radical include 2-hydroxyethoxy, 2-hydroxypropoxy,1-hydroxyprop-2-yloxy and 3-hydroxypropoxy. An analogous conventionapplies to other generic terms.

Within the present invention it is to be understood that a quinazolinederivative of the formula I may exhibit the phenomenon of tautomerismand that the formulae drawings within this specification can representonly one of the possible tautomeric forms. It is to be understood thatthe invention encompasses any tautomeric form which possessesanti-proliferative activity and is not to be limited merely to any onetautomeric form utilised within the formulae drawings.

The quinazolines of the formula I are unsubstituted at the 2-positionthus it is to be understood that the R¹ groups are located only on thebenzo portion of the quinazoline ring.

It is also to be understood that certain quinazoline derivatives of theformula I can exist in solvated as well as unsolvated forms such as, forexample, hydrated forms. It is to be understood that the inventionencompasses all such solvated forms which possess anti-proliferativeactivity.

Suitable values for the generic radicals referred to above include thoseset out below.

A suitable value for a substituent on Q¹, Q² or Q³, for a substituent ona CH₂ group within a substituent on Q¹, or for R¹, R², R³ or R⁴ when itis halogeno is, for example, fluoro, chloro, bromo or iodo;

when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropylor butyl;

when it is (1-4C)alkoxy is, for example, methoxy, ethoxy, propoxy.isopropoxy or butoxy;

when it is (1-4C)alkylamino is, for example, methylamino, ethylamino orpropylamino;

when it is di-[(1-4C)alkyl]amino is, for example, dimethylamino,diethylamino, N-ethyl-N-methylamino or dipropylamino;

when it is (2-4C)alkanoylamino is, for example, acetamido, propionamidoor butyramido;

when it is (1-4C)alkoxycarbonyl is, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, butoxcarbonyl or tert-butoxycarbonyl;

when it is N-(1-4C)alkylcarbamoyl is, for example, N-methylcarbamoyl orN-ethylcarbamoyl;

and when it is N,N-di-[(1-4C)alkyl]carbamoyl is, for example,N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl andN,N-diethylcarbamoyl.

Suitable values for each substituent which may be present on Q¹ include,for example:

for (2-4C)alkenyloxy: vinyloxy and allyloxy;

for (2-4C)alkynyloxy: 2-propynyloxy;

for (1-3C)alkylenedioxy: methylenedioxy, ethylenedioxy andpropylenedioxy;

for 4-(1-4C)alkylpiperazin-1-yl: 4-methylpiperazin-1-yl and4-ethylpiperazin-1-yl;

for amino-(1-4C)alkyl: aminomethyl, 2-aminoethyl and 3-aminopropyl;

for (1-4C)alkylamino-(1-4C)alkyl: methylaminomethyl, 2-methylaminoethyland 3-methylaninopropyl;

for di-[(1-4C)alkyl]amino-(1-4C)alkyl: dimethylaminoethyl,diethylaminomethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl and3-dimethylaminopropyl;

for pyrrolidin-1-yl-(1-4C)alkyl: pyrrolidin-1-ylmethyl,2-pyrrolidin-1-ylethyl and 3-pyrrolidin-1-ylpropyl;

for piperidino-(1-4C)alkyl: piperidinomethyl, 2-piperidinoethyl and3-piperidinopropyl;

for morpholino-(1-4C)alkyl: morpholinomethyl, 2-morpholinoethyl and3-morpholinopropyl;

for piperazin-1-yl-(1-4C)alkyl: piperazin-1-ylmethyl,2-piperazin-1-ylethyl and 3-piperazin-1-ylpropyl;

for 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl:4-methylpiperazin-1-ylmethyl, 2-(4-methylpiperazin-1-yl)ethyl and3-(4-methylpiperazin-1-yl)propyl;

for halogeno-(2-4C)alkoxy: 2-fluoroethoxy, 2-chloroethoxy,2-bromoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 2,2,2-trifluoroethoxy,1,1,2,2,2-pentafluoroethoxy, 2,2,3,3-tetrafluoropropoxy,2,2,3,3,3-pentafluoropropoxy and 1,1,2,2,3,3,3-heptafluoropropoxy,

for hydroxy-(2-4C)alkoxy: 2-hydroxyethoxy, 3-hydroxypropoxy and4-hydroxybutoxy;

for (1-4C)alkoxy-(2-4C)alkoxy: 2-methoxyethoxy, 2-ethoxyethoxy,3-methoxypropoxy and 3-ethoxypropoxy;

for amino-(2-4C)alkoxy: 2-aminoethoxy and 3-aminopropoxy;

for (1-4C)alkylamino-(2-4C)alkoxy: 2-methylaminoethoxy,2-ethylaminoethoxy, 2-propylaminoethoxy, 3-methylaminopropoxy and3-ethylaminopropoxy;

for di-[(1-4C)alkyl]amino-(2-4C)alkoxy: 2-dimethylaminoethoxy,2-(N-ethyl-N-methylamino)ethoxy, 2-diethylaminoethoxy,2-dipropylaminoethoxy, 3-dimethylaminopropoxy and 3-diethylaminopropoxy;

for pyrrolidin-1-yl-(2-4C)alkoxy: 2-(pyrrolidin-1-yl)ethoxy and3-(pyrrolidin-1-yl)propoxy;

for piperidino-(2-4C)alkoxy: 2-piperidinoethoxy and 3-piperidinopropoxy;

for morpholino-(2-4C)alkoxy: 2-morpholinoethoxy and 3-morpholinopropoxy;

for piperazin-1-yl-(2-4C)alkoxy: 2-(piperazin-1-yl)ethoxy and3-(piperazin-1-yl)propoxy;

for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy:2-(4-methylpiperazin-1-yl)ethoxy and 3-(4-methylpiperazin-1-yl)propoxy;

for (1-4C)alkylthio-(2-4C)alkoxy: 2-methylthioethoxy and3-methylthiopropoxy;

for (1-4C)alkylsulphinyl-(2-4C)-alkoxy: 2-methylsulphinylethoxy and3-methylsulphinylpropoxy;

for (1-4C)alkylsulphonyl-(2-4C)alkoxy: 2-methylsulphonylethoxy and3-methylsulphonylpropoxy;

for halogeno-(2-4C)alkylamino: 2-fluoroethylamino, 2-chloroethylamino,2-bromoethylamino, 3-fluoropropylamino and 3-chloropropylamino;

for hydroxy-(2-4C)alkylamino: 2-hydroxyethylamino, 3-hydroxypropylaminoand 4-hydroxybutylamino;

for (1-4C)alkoxy-(2-4C)alkylamino: 2-methoxyethylamino,2-ethoxyethylamino, 3-methoxypropylamino and 3-ethoxypropylamino;

for amino-(2-4C)alkylamino: 2-aminoethylamino, 3-aminopropylamino and4-aminobutylamino;

for (1-4C)alkylamino(2-4C)alkylamino: 2-methylaminoethylamino,2-ethyl-aminoethylamino, 2-propylaminoethylamino,3-methylaminopropylamino, 3-ethylaminopropylamino and4-methylaminobutylamino;

for di-[(1-4C)alkyl]amino-(2-4C)alkylamino: 2-dimethylaminoethylamino,2-(N-ethyl-N-methylamino)ethylamino, 2-diethylaminoethylamino,2-dipropylaminoethylamino, 3-dimethylaminopropylamino,3diethylaminopropylamino and 4-dimethylaminobutylamino;

for pyrrolidin-1-yl-(2-4C)alkylamino: 2-(pyrrolidin-1-yl)ethylamino and3-(pyrrolidin-1-yl)propylamino;

for piperidino-(2-4C)alkylamino: 2-piperidinoethylamino and3-piperidinopropylamino;

for morpholino2-4C)alkylamino: 2-morpholinoethylamino and3-morpholinopropylamino;

for piperazin-1-yl-(2-4C)alkylamino: 2-(piperazin-1-yl)ethylamino and3-(piperazin-1-yl)propylamino;

for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino:2-(4-methylpiperazin-1-yl)ethylamino and3-(4-methylpiperazin-1-yl)propylamino;

for N-(1-4C)alkyl-halogeno-(2-4C)alkylamino:N-(2-chloroethyl)-N-methylamino, N-(2-bromoethyl)-N-methylamino andN-(2-bromoethyl)-N-ethylamino;

for N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino:N-(2-hydroxyethyl)-N-methylamino, N-(3-hydroxypropyl)-N-methylamino andN-ethyl-N-(2-hydroxyethyl)amino;

for N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino:N-methyl-N-(2-methoxyethyl)amino, N-methyl-N-(3-methoxypropyl)amino andN-ethyl-N-(2-methoxyethyl)amino;

for halogeno-(2-4C)alkanoylamino: 2-chloroacetamido, 2-bromoacetamido,3-chloropropionamido and 3-bromopropionamido;

for hydroxy-(2-4C)alkanoylamino: 2-hydroxyacetamido,3-hydroxypropionamido and 4-hydroxybutyramido;

for (1-4C)alkoxy-(2-4C)alkanoylamino: 2-methoxyacetamido,2-ethoxyacetamido, 2-propoxyacetamido, 3-methoxypropionamido,3-ethoxypropionamido and 4-methoxybutyramido;

for (3-4C)alkenoylamino: acrylamido, methacrylamido, crotonamido andisocrotonamido;

for (34C)alkynoylamino: propiolamido;

for amino-(2-4C)alkanoylamino: 2-aminoacetamido. 2-aminopropionamido and3-aminopropionamido;

for (1-4C)alkylamino-(2-4C)alkanoylamino: 2-methylaminoacetamido,2-ethylaminoacetamido, 2-methylaminopropionamido and3-methylaminopropionamido;

for di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino: 2-dimethylaminoacetamido,2-diethylaminoacetamido, 2-dimethylaminopropionamido and3-dimethylaminopropionamido;

for pyrrolidin-1-yl-(2-4C)alkanoylamino: 2-pyrrolidin-1-ylacetamido,2-pyrrolidin-1-ylpropionamido and 3-pyrrolidin-1-ylpropionamido;

for piperidino-(2-4C)alkanoylamino: 2-piperidinoacetamido,2-piperidinopropionamido and 3-piperidinopropionamido;

for morpholino-(2-4C)alkanoylamino: 2-morpholinoacetamido,2-morpholinopropionamido and 3-morpholinopropionamido;

for piperazin-1-yl-(2-4C)alkanoylamino: 2-piperazin-1-ylacetamido,2-piperazin-1-ylpropionamido and 3-piperazin-1-ylpropionamido;

for 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino:2-(4-methylpiperazin-1-yl)acetamido,2-(4-methylpiperazin-1-yl)propionamido and3-(4-methylpiperazin-1-yl)propionamido.

When there is a (1-3C)alkylenedioxy substituted on Q¹, the oxygen atomsthereof occupy adjacent positions on the Q¹ ring.

When m is 1 the R¹ substituent is preferably located at the 7-positionof the quinazoline ring.

Suitable substituents formed when any of the substituents on Q¹comprising a CH₂ group which is not attached to a halogeno, SO or SO₂group or to a N, O or S atom bears on said CH₂ group a substituentselected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino anddi-[(1-4C)alkyl]amino include, for example, substituted(1-4C)alkylamino-(2-4C)alkoxy or di-[(1-4C)alkyl]amino-(2-4C)alkoxygroups, for example hydroxy-(1-4C)alkylamino-(2-4C)alkoxy orhydroxy-di-[(1-4C)alkyl]amino-(2-4C)alkoxy groups such as3-methylamino-2-hydroxypropoxy and 3-dimethylamino-2-hydroxypropoxy.

A suitable value for Q¹ and Q³ when it is a naphthyl group is, forexample, 1-naphthyl or 2-naphthyl.

A suitable value for Q¹ or Q³ when it is a 5- or 6-membered heteroarylmoiety containing up to 3 heteroatoms selected from oxygen, nitrogen andsulphur, which is a single ring is, for example, furyl, pyrrolyl,thienyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl,thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl orthiadiazoylyl, or which is fused to a benzo ring is, for example,benzofuryl, indolyl, benzothienyl, quinolyl. isoquinolyl, benzoxazolyl,indazolyl, benzimidazolyl, benzothiazolyl, cinnolinyl, quinazolinyl,quinoxalinyl or benzotriazolyl. Said heteroaryl moiety may be attachedto X¹ and X² through any available position. The optional substituentson Q¹ or Q³ may be located at any available position including on anyavailable nitrogen heteroatom.

A suitable value for Q² when it is 9- or 10-membered bicyclicheterocyclic moiety containing 1 or 2 nitrogen heteroatoms andoptionally containing a further heteroatom selected from nitrogen,oxygen and sulphur is, for example, a benzo-fused heterocyclic moietysuch as indolyl, isoindolyl, indolizinyl, 1H-benzimidazolyl,1H-indazolyl, benzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl,benzothiazolyl, benzo[c]isothiazolyl, benzo[d]isothiazolyl,1H-benzotriazolyl, benzo[c]furazanyl, benzo[c][2,1,3]thiadiazolyl,benzo[d][1,2,3]oxadiazolyl, benzo[d][1,2,3]thiadiazolyl, quinolyl,1,2-dihydroquinolinyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, 4H-1,4-benzoxazinyl or4H-1,4-benzothiazinyl.

The heterocyclic moiety may be attached through any available positionincluding from either of the two rings of the bicyclic heterocyclicmoiety. The heterocyclic moiety may bear a suitable substituent such asa (1-4C)alkyl substituent on an available nitrogen atom.

It is also to be understood that, within the structure of formula I,when X¹ is, for example, a group of the formula C(R²)₂O, it is the Catom which is attached to the quinazoline ring and the O atom which isattached to Q¹. Likewise, when X² is, for example, a group of theformula N(R³)SO₂, it is the N atom which is attached to the phenylenering and the SO₂ group which is attached to Q³. Likewise, when X¹ is,for example, a group of the formula CON(R²), it is the CO group which isattached to the quinazoline ring and the N atom which is attached to Q¹.

A suitable pharmaceutically-acceptable salt of a quinazoline derivativeof the invention is, for example, an acid-addition salt of a quinazolinederivative of the invention which is sufficiently basic, for example, amono- or di-acid-addition salt with, for example, an inorganic ororganic acid, for example hydrochloric, hydrobromic, sulphuric,phosphoric, trifluoroacetic, citric or maleic acid. In addition asuitable pharmaceutically-acceptable salt of a quinazoline derivative ofthe invention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically-acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Particular novel compounds of the invention include, for example,quinazoline derivatives of the formula I, or pharmaceutically-acceptablesalts thereof, wherein, unless otherwise stated, each of Q¹, X¹, m, R¹and Q² has any of the meanings defined hereinbefore or in this sectionconcerning particular compounds of the invention:

(a) X¹ is a direct link;

(b) X¹ is a group of the formula CO, CH₂, CH(OH), CH₂CH₂, CH═CH, C≡C, O,S, SO, SO₂, NH, CONH, SO₂NH, NHCO, NHSO₂, OCH₂, SCH₂, NHCH₂, CH₂O, CH₂Sor CH₂NH;

(c) X¹ is a group of the formula CH₂, CH₂CH₂, O, S, SO, SO₂, NH, NHCO,NHSO₂, OCH₂ or NHCH₂;

(d) Q¹ is phenyl optionally substituted as defined hereinbefore;

(e) Q¹ is a 5- or 6-membered monocyclic heteroaryl moiety containing upto 3 heteroatoms selected from oxygen, nitrogen and sulphur which isoptionally substituted as defined hereinbefore;

(f) Q¹ is furyl, pyrrolyl, thienyl, pyridyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, 1,2,3-triazolyl or 1,2,4-triazolyl which is attached fromany available position including from a nitrogen atom and which isoptionally substituted as defined hereinbefore;

(g) Q¹ bears no optional substituents;

(h) Q¹ bears 1 or 2 substituents selected from halogeno, hydroxy, amino,trifluoromethoxy, trifluoromethyl, cyano, nitro, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and(2-4C)alkanoylamino;

(i) Q¹ bears a substituent selected from amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl;

(j) m is 1 and R¹ is hydrogen;

(k) m is 1 and R¹ is (1-4C)alkoxy;

(l) Q² is phenyl which is optionally substituted as definedhereinbefore;

(m) Q² is a group of the formula II

wherein X² is a group of the formula CO, CH₂, CH(OH), S, SO₂NH or OCH₂,Q³ is phenyl or pyridyl which optionally bears 1 or 2 substituentsselected from halogeno, (1-4C)alkyl and (1-4C)alkoxy, n is 1 and R⁴ ishydrogen, halogeno, (1-4C)alkyl or (1-4C)alkoxy;

(n) Q² is a group of the formula II wherein X² is a group of the formulaCO, Q³ is phenyl which optionally bears 1 or 2 substituents selectedfrom halogeno, (1-4C)alkyl and (1-4C)alkoxy, n is 1 and R⁴ is hydrogen,halogeno or (1-4C)alkyl; and

(o) Q² is a group of the formula 11 wherein X² is a group of the formulaOCH₂, Q³ is pyridyl, n is 1 and R⁴ is hydrogen. halogeno or (1-4C)alkyl;provided that when Q¹ is optionally-substituted phenyl, X¹ is notN(R²)CO, N(R²)SO₂, OC(R²)₂, N(R²)C(R²)₂, C(R²)₂S or C(R²)₂N(R²); andwhen X¹ is a direct link, Q¹ is not a 5- or 9-membered nitrogen-linkedheteroaryl moiety containing up to 3 nitrogen heteroatoms.

A preferred compound of the invention is a quinazoline derivative of theformula I

wherein X¹ is a direct link or a group of the formula CH₂, CH₂CH₂, NH,NHCO, NHSO₂, OCH₂, SCH₂, NHCH₂, CH₂O or CH₂S;

Q¹ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-oxazolyl, 4-oxazolyl, 5-isoxazolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-isothiazolyl or1,2,3-triazol-4-yl which optionally bears a substituent selected frommethyl, aminomethyl, 2-aminoethyl, methylaminomethyl,2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl,pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl,2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1, 2 or 3 substituents selectedfrom fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy,

or Q² is a group of the formula II

wherein X² is a group of the formula CO or OCH₂, Q³ is phenyl or2-pyridyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro, bromo, methyl and methoxy, n is 1 and R⁴ is hydrogen,fluoro, chloro, bromo or methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the formula I

wherein X¹ is a direct link or a group of the formula NHCO, OCH₂ orNHCH₂;

Q¹ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-oxazolyl, 5-isoxazolyl or 4-imidazolyl which optionally bears asubstituent selected from aminomethyl, morpholinomethyl and2-morpholinoethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1 or 2 substituents selectedfrom fluoro, chloro, bromo and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A specific especially preferred compound of the invention is thequinazoline derivative of the formula I:

4-(3-chloro-4-fluoroanilino)-6-(3-furyl)quinazoline,4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline,4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline,4-(3-chloro-4-fluoroanilino)-6-(5-morpholinomethylthien-3-yl)quinazolineor4-(3-chloro-4-fluoroanilino)-7-methoxy6-(3-pyridylmethoxy)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the formula I

wherein X¹ is a direct link;

Q¹ is thienyl which bears a substituent selected from amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl;

m is 1 and R¹ is hydrogen;

and Q² is phenyl which optionally bears up to 3 substituents selectedfrom halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro, carboxy,carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl;

or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the formula I

wherein X¹ is a direct link;

Q¹ is 2-thienyl which optionally bears a substituent selected frommethyl, aminomethyl, 2-aminoethyl, methylaminomethyl,2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl,pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl,2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1, 2 or 3 substituents selectedfrom fluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the formula I

wherein X¹ is a direct link;

Q¹ is 2-thienyl which optionally bears a substituent selected fromaminomethyl, morpholinomethyl and 2-morpholinoethyl;

m is 1 and R¹ is hydrogen or methoxy;

and Q² is phenyl which optionally bears 1 or 2 substituents selectedfrom fluoro, chloro, bromo and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific especially preferred compound of the invention is thequinazoline derivative of the formula I:

4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the formula I wherein X¹ is a direct link or a group ofthe formula O;

Q¹ is phenyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro, bromo, amino, cyano, nitro, aminomethyl,methylaminomethyl, dimethylaminomethyl, diethylaminomethyl,pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-methylpiperazin-1-ylmethyl;

m is 1 and R¹ is hydrogen or methoxy; and

Q² is phenyl which optionally bears 1, 2 or 3 substituents selected fromfluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy,

or Q² is a group of the formula II

wherein X² is a group of the formula OCH₂, Q³ is 2-pyridyl, n is 1 andR⁴ is hydrogen, fluoro, chloro or methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further preferred compound of the invention is a quinazolinederivative of the formula I wherein X¹ is a direct link or a group ofthe formula O;

Q¹ is phenyl which optionally bears 1 or 2 substituents selected fromamino, aminomethyl, diethylaminomethyl, pyrrolidin-1-ylmethyl,piperidinomethyl and morpholinomethyl;

m is 1 and R¹ is hydrogen; and

Q² is phenyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro and methyl;

or a pharmaceutically-acceptable acid-addition salt thereof.

A further specific especially preferred compound of the invention is thequinazoline derivative of the formula I:

4-(3-methylanilino)-6-phenylquinazoline,6-(4-aminomethylphenyl)-4-(3-chloro-4-fluoroanilino)quinazoline,6-(4-aminophenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline,6-(4-aminomethylphenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline or4-(3-chloro-4-fluoroanilino)-6-(4-morpholinomethylphenoxy)quinazoline;

or a pharmaceutically-acceptable acid-addition salt thereof.

A quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of chemically-relatedcompounds. Suitable processes include, for example, those illustrated inEuropean Patent Applications Nos. 0520722, 0566226, 0602851, 0635507 and0635498, and International Patent Applications WO 96/15118 and WO96/16960. Such processes, when used to prepare a quinazoline derivativeof the formula I, or a pharmaceutically-acceptable salt thereof, areprovided as a further feature of the invention and are illustrated bythe following representative examples in which, unless otherwise stated,X¹, Q¹, m, R¹ and Q² have any of the meanings defined hereinbefore for aquinazoline derivative of the formula I. Necessary starting materialsmay be obtained by standard procedures of organic chemistry. Thepreparation of such starting materials is described within theaccompanying non-limiting Examples. Alternatively necessary startingmaterials are obtainable by analogous procedures to those illustratedwhich are within the ordinary skill of an organic chemist.

(a) The reaction, conveniently in the presence of a suitable base, of aquinazoline of the formula III

wherein Z is a displaceable group, with an aniline of the formulaQ²—NH₂.

A suitable base is, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkalineearth metal carbonate or hydroxide, for example sodium carbonate,potassium carbonate, calcium carbonate, sodium hydroxide or potassiumhydroxide, or, for example, an alkali metal hydride, for example sodiumhydride.

A suitable displaceable group Z is, for example, a halogeno, alkoxy,aryloxy or sulphonyloxy group, for example a chloro, bromo, methoxy,phenoxy, methanesulphonyloxy or toluene-4-sulphonyloxy group. Thereaction is conveniently carried out in the presence of a suitable inertsolvent or diluent, for example an alkanol or ester such as methanol,ethanol, isopropanol or ethyl acetate, a halogenated solvent such asmethylene chloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or adipolar aprotic solvent such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide.The reaction is conveniently carried out at a temperature in the range,for example, 10 to 250° C., preferably in the range 40 to 80° C.

The quinazoline derivative of the formula I may be obtained from thisprocess in the form of the free base or alternatively it may be obtainedin the form of a salt with the acid of the formula H—Z wherein Z has themeaning defined hereinbefore. When it is desired to obtain the free basefrom the salt, the salt may be treated with a suitable base, forexample, an organic amine base such as, for example, pyridine.2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or,for example, an alkali or alkaline earth metal carbonate or hydroxide,for example sodium carbonate, potassium carbonate, calcium carbonate,sodium hydroxide or potassium hydroxide.

(b) For the preparation of those compounds of the formula I wherein X¹is a direct link, the reaction, conveniently in the presence of asuitable catalyst, of a quinazoline of the formula IV

wherein Z is a displaceable group as defined hereinbefore, with anorganoboron reagent of the formula Q¹—B(L¹)(L²) wherein each L¹ and L²,which may be the same or different, is a suitable ligand.

A suitable value for the ligands L¹ and L² which are present on theboron atom include, for example, a hydroxy, (1-4C)alkoxy or (1-6C)alkylligand, for example a hydroxy, methoxy, ethoxy, propoxy, isopropoxy,butoxy, methyl, ethyl, propyl, isopropyl or butyl ligand. Alternativelythe ligands L¹ and L² may be linked such that, together with the boronatom to which they are attached, they form a ring. For example, L¹ andL² together may define an oxy-(2-4C)alkylene-oxy group, for example anoxyethyleneoxy or oxytrimethyleneoxy group such that, together with theboron atom to which they are attached, they form a cyclic boronic acidester group. Particularly suitable organoboron reagents include, forexample, compounds of the formulae Q¹—B(OH)₂, Q¹—B(OPr^(i))₂ andQ¹—B(Et)₂.

A suitable catalyst for the reaction includes, for example, a metalliccatalyst such as a palladium(0), palladium(II), nickel(0) or nickel(II)catalyst, for example tetrakis(triphenylphosphine)palladium(0),palladium(II) chloride, palladium(II) bromide,bis(triphenylphosphine)palladium(II) chloride,tetrakis(triphenylphosphine)nickel(0), nickel(II) chloride, nickel(II)bromide or bis(triphenylphosphine)nickel(II) chloride. In addition afree radical initiator may conveniently be added, for example an azocompound such as azo(bisisobutyronitrile).

The reaction is conveniently carried out in the presence of a suitableinert solvent or diluent, for example an ether such as tetrahydrofuran,1,4-dioxan or 1,2-dimethoxyethane, an aromatic solvent such as benzene,toluene or xylene, or an alcohol such as methanol or ethanol, and thereaction is conveniently carried out at a temperature in the range, forexample 10 to 250° C., preferably in the range 60 to 120° C.

Organoboron reagents of the formula Q¹—B(L¹)(L²) may be obtained bystandard procedures of organic chemistry which are within the ordinaryskill of an organic chemist, for example by the reaction of anorganometallic compound of the formula Q¹—M, wherein M is, for example,lithium or the magnesium halide portion of a Grignard reagent, with anorganoboron compound of the formula Z—B(L¹)(L²) wherein Z is adisplaceable group as defined hereinbefore. Preferably the compound ofthe formula Z—B(L¹)(L²) is, for example, boric acid or a tri-(1-4C)alkylborate such as tri-isopropyl borate.

In an alternative procedure the organoboron compound of the formulaQ¹—B(L¹)(L²) may be replaced with an organometallic compound of theformula Q¹—M wherein M is a metal atom or a metallic group (i.e. a metalatom bearing suitable ligands). Suitable values for the metal atominclude, for example, lithium and copper. Suitable values for themetallic group include, for example, groups which contain a tin,silicon, zirconium, aluminium, magnesium or mercury atom. Suitableligands within such a metallic group include, for example, hydroxygroups, (1-6C)alkyl groups such as methyl, ethyl, propyl, isopropyl andbutyl groups, halogeno groups such as chloro, bromo and iodo groups, and(1-6C)alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy andbutoxy groups. A particular organometallic compound of the formula Q¹—Mis, for example, an organotin compound such as a compound of the formulaQ¹—SnBu₃, an organosilicon compound such as a compound of the formulaQ¹—Si(Me)F₂, an organozirconium compound such as a compound of theformula Q¹—ZrCl₃, an organoaluminium compound such as a compound of theformula Q¹-AlEt₂, an organomagnesium compound such as a compound of theformula Q¹—MgBr, or an organomercury compound such as a compound of theformula Q¹—HgBr.

(c) For the preparation of those compounds of the formula I wherein X¹is a direct link, the reaction, conveniently in the presence of asuitable catalyst as defined hereinbefore, of a quinazoline of theformula V

wherein each of L¹ and L², which may be the same or different, is asuitable ligand as defined hereinbefore, with a compound of the formulaQ¹—Z wherein Z is a displaceable group as defined hereinbefore.

The reaction is conveniently carried out in a suitable inert solvent ordiluent and at a suitable temperature in an analogous manner to theconditions described in paragraph (b) hereinbefore.

The quinazoline of the formula V may conveniently be obtained byanalogous procedures to those described hereinbefore for the preparationof the organoboron reagent of the formula Q¹—B(L¹)(L²).

(d) For the production of those compounds of the formula I wherein X¹ isa group of the formula N(R²)CO or N(R²)SO₂, the acylation of an amine ofthe formula VI

with a carboxylic acid of the formula Q¹—CO₂H, or a reactive derivativethereof, or a sulphonic acid of the formula Q¹—SO₂OH, or a reactivederivative thereof, as appropriate.

A suitable reactive derivative of a carboxylic acid of the formulaQ¹—CO₂H is, for example, an acyl halide, for example an acyl chlorideformed by the reaction of the acid and an inorganic acid chloride, forexample thionyl chloride; a mixed anhydride, for example an anhydrideformed by the reaction of the acid and a chloroformate such as isobutylchloroformate; an active ester, for example an ester formed by thereaction of the acid and a phenol such as pentafluorophenol, an estersuch as pentafluorophenyl trifluoroacetate or an alcohol such asmethanol, ethanol, isopropanol, butanol or N-hydroxybenzotriazole; anacyl azide, for example an azide formed by the reaction of the acid andazide such as diphenylphosphoryl azide; an acyl cyanide, for example acyanide formed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidand a carbodiimide such as dicyclohexylcarbodiimide. Analogouslysuitable reactive derivatives of the sulphonic acid of the formulaQ¹—SO₂OH may be obtained.

The reaction is conveniently carried out in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0 to 120° C., preferably at or near ambient temperature.

(e) For the production of those compounds of the formula I wherein X¹ isa group of the formula OC(R²)₂, SC(R²)₂ or N(R²)C(R²)₂, the alkylation,conveniently in the presence of a suitable base as defined hereinbefore,of an appropriate phenol, thiophenol or aniline with an alkylating agentof the formula Z—C(R²)₂—Q¹ wherein Z is a displaceable group as definedhereinbefore.

The reaction is conveniently carried out in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 10 to 150° C., preferably at or near 80° C.

(f) For the production of those compound of the formula I wherein X¹ isa group of the formula C(R²)₂O, C(R²)₂S or C(R²)₂N(R²), the alkylation,conveniently in the presence of a suitable base as defined hereinbefore,of the appropriate phenol of the formula HO—Q¹, thiophenol of theformula HS—Q¹ or aniline of the formula R²NH—Q¹, with an alkylatingagent of the formula VII

wherein Z is a displaceable group as defined hereinbefore.

The reaction is conveniently carried out in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0 to 150° C., preferably in the range 20 to 70° C.

(g) For the production of those compounds of the formula I which possessan aminomethyl substituent or wherein X¹ is a group of the formulaN(R²)CH₂ or CH₂N(R²), the reduction of a compound of the formula I whichpossesses a cyano substituent or wherein X¹ is a group of the formulaN(R²)CO or CON(R²) as appropriate.

The reduction may be carried out by any of the many procedures known inthe art for such transformations. A suitable reducing agent is, forexample, an alkali metal aluminium hydride such as lithium aluminiumhydride.

The reduction is conveniently carried out in a suitable inert solvent ordiluent such as diethyl ether or tetrahydrofuran and at a temperature inthe range, for example, 0 to 80° C., preferably in the range 15 to 50°C.

(h) For the production of those compounds of the formula I which possessan amino substituent, the reduction of a compound of the formula I whichpossesses a nitro substituent.

The reduction may conveniently be carried out by any of the manyprocedures known for such a transformation. The reduction may be carriedout, for example, by the hydrogenation of a solution of the nitrocompound in an inert solvent or diluent as defined hereinbefore in thepresence of a suitable metal catalyst such as palladium or platinum. Afurther suitable reducing agent is, for example, an activated metal suchas activated iron (produced by washing iron powder with a dilutesolution of an acid such as hydrochloric acid). Thus, for example, thereduction may be carried out by heating a mixture of the nitro compoundand the activated metal in a suitable solvent or diluent such as amixture of water and an alcohol, for example, methanol or ethanol, to atemperature in the range, for example, 50 to 150° C., conveniently at ornear 70° C.

(i) For the production of those compounds of the formula I wherein X¹ isa group of the formula NHCH(R²), the reductive amination of a ketocompound of the formula R²—CO—Q¹ with an amine of the formula VIII

Any reducing agent known in the art for promoting a reductive aminationreaction may be employed. A suitable reducing agent is, for example, ahydride reducting agent, for example an alkali metal aluminium hydridesuch as lithium aluminium hydride or, preferably, an alkali metalborohydride such as sodium borohydride, sodium cyanoborohydride, sodiumtriethylborohydride, sodium trimethoxyborohydride and sodiumtriacetoxyborohydride. The reaction is conveniently performed in asuitable inert solvent or diluent, for example tetrahydrofuran anddiethyl ether for the more powerful reducing agents such as lithiumaluminium hydride, and, for example, methylene chloride or a proticsolvent such as methanol and ethanol for the less powerful reducingagents such as sodium triacetoxyborohydride and sodium cyanoborohydride.The reaction is performed at a temperature in the range, for example, 10to 80° C, conveniently at or near ambient temperature.

(j) For the production of those compounds of the formula I wherein X¹ isa group of the formula O, S or N(R²), the coupling, conveniently in thepresence of a suitable base as defined hereinbefore, of an appropriatephenol, thiophenol or aniline with a compound of the formula Z—Q¹wherein Z is a displaceable group as defined hereinbefore.

Conveniently the reaction may be performed in the presence of a suitablecatalyst, for example a metallic catalyst such as a palladium(0) orcopper(I) catalyst, for exampletetrakis(triphenylphosphine)palladium(0), cuprous chloride or cuprousbromide.

The coupling reaction is conveniently performed in a suitable inertsolvent or diluent as defined hereinbefore, preferably inN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, 10 to 150° C., conveniently at or near 100° C.

When a pharmaceutically-acceptable salt of a quinazoline derivative ofthe formula I is required, for example a mono- or di-acid-addition salt,it may be obtained, for example, by reaction of said compound with, forexample, a suitable acid using a conventional procedure.

As stated hereinbefore the quinazoline derivative defined in the presentinvention possesses anti-proliferative activity such as anti-canceractivity which is believed to arise from the Class I receptor tyrosinekinase inhibitory activity of the compound. These properties may beassessed, for example, using one or more of the procedures set outbelow:

(a) An in vitro assay which determines the ability of a test compound toinhibit the enzyme EGF receptor tyrosine kinase. Receptor tyrosinekinase was obtained in partially purified form from A431 cells (derivedfrom human vulval carcinoma) by the procedures described below which arerelated to those described by Carpenter et al., J. Biol. Chem., 1979,254, 4884, Cohen et al., J. Biol Chem., 1982, 257, 1523 and by Braun etal., J. Biol. Chem., 1984, 259, 2051.

A-431 cells were grown to confluence using Dulbecco's modified Eagle'smedium DMEM) containing 5% fetal calf serum (FCS). The obtained cellswere homogenised in a hypotonic borate/EDTA buffer at pH 10.1. Thehomogenate was centrifuged at 400 g for 10 minutes at 0-4° C. Thesupernatant was centrifuged at 25,000 g for 30 minutes at 0-4° C. Thepelleted material was suspended in 30 mM Hepes buffer at pH 7.4containing 5% glycerol, 4 mM benzamidine and 1% Triton X-100, stirredfor 1 hour at 0-4° C., and recentrifuged at 100,000 g for 1 hour at 0-4°C. The supernatant, containing solubilised receptor tyrosine kinase, wasstored in liquid nitrogen.

For test purposes 40 μl of the enzyme solution so obtained was added toa mixture of 400 μl of a mixture of 150 mM Hepes buffer at pH 7.4, 500μM sodium orthovanadate, 0.1% Triton X-100, 10% glycerol, 200 μl water,80 μl of 25 mM DTT and 80 μl of a mixture of 12.5 mM manganese chloride,125 mM magnesium chloride and distilled water. There was thus obtainedthe test enzyme solution.

Each test compound was dissolved in dimethylsulphoxide (DMSO) to give a50 mM solution which was diluted with 40 mM Hepes buffer containing 0.1%Triton X-100, 10% glycerol and 10% DMSO to give a 500 μM solution. Equalvolumes of this solution and a solution of epidermal growth factor (EGF;20 μg/ml) were mixed.

[γ-³²P]ATP (3000 Ci/mM, 250 μCi) was diluted to a volume of 2 ml by theaddition of a solution of ATP (100 μM) in distilled water. An equalvolume of a 4 mg/ml solution of the peptideArg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly in a mixture of 40mM Hepes buffer at pH 7.4, 0.1% Triton X-100 and 10% glycerol was added.

The test compound/EGF mixture solution (5 μl) was added to the testenzyme solution (10 μl) and the mixture was incubated at 0-4° C. for 30minutes. The ATP/peptide mixture (10 μl) was added and the mixture wasincubated at 25° C. for 10 minutes. The phosphorylation reaction wasterminated by the addition of 5% trichloroacetic acid (40 μl) and bovineserum albumin (BSA; 1 mg/ml, 5 μl). The mixture was allowed to stand at4° C. for 30 minutes and then centrifuged. An aliquot (40 μl) of thesupernatant was placed onto a strip of Whatman p 81 phosphocellulosepaper. The strip was washed in 75 mM phosphoric acid (4×10 ml) andblotted dry. Radioactivity present in the filter paper was measuredusing a liquid scintillation counter (Sequence A). The reaction sequencewas repeated in the absence of the EGF (Sequence B) and again in theabsence of the test compound (Sequence C).

Receptor tyrosine kinase inhibition was calculated as follows:${\% \quad {Inhibition}} = {\frac{100 - \left( {A - B} \right)}{C - B} \times 100}$

The extent of inhibition was then determined at a range ofconcentrations of test compound to give an IC₅₀ value.

(b) An in vitro assay which determines the ability of a test compound toinhibit the EGF-stimulated growth of the human naso-pharyngeal cancercell line KB.

KB cells were seeded into wells at a density of 1×10⁴-1.5×10⁴ cells perwell and grown for 24 hours in DMEM supplemented with 5% FCS(charcoal-stripped). Cell growth was determined after incubation for 3days by the extent of metabolism of MTT tetrazolium dye to furnish abluish colour. Cell growth was then determined in the presence of EGF(10 ng/ml) or in the presence of EGF (10 ng/ml) and a test compound at arange of concentrations. An IC₅₀ value could then be calculated.

(c) An in vivo assay in a group of male rats which determines theability of a test compound (usually administered orally as a ball-milledsuspension in 0.5% polysorbate) to inhibit the stimulation of liverhepatocyte growth caused by the administration of the growth factor TGFα(400 μg/kg subcutaneously, usually dosed twice, 3 and 7 hoursrespectively after the administration of the test compound).

In a control group of rats, the administration of TGFα causes on averagea 5-fold stimulation of liver hepatocyte growth.

Cell-growth in the control and test animals is determined as follows:

On the morning of the day after the dosing of the test compound (or 0.5%polysorbate in the control group), the animals are dosed withbromodeoxyuridine (BrdU; 100 mg/kg intraperitoneally). The animals arekilled four hours later and the livers are excised. Slices are cut fromeach liver and the uptake of BrdU is determined by a conventionalimmunohistochemical technique similar to that described on pages 267 and268 of an article by Goldsworthy et al. in Chemically Induced CellProliferation: Implications for Risk Assessment, Wiley-Liss Inc., 1991,pages 253-284. Further tests were carried out using a range of doses ofthe test compounds to allow the calculation of an approximate ED₅₀ valuefor the inhibition of liver hepatocyte proliferation as determined byinhibition of the uptake of BrdU.

(d) An in-vivo assay in a group of athymic nude mice (strain ONU:Alpk)which determines the ability of a test compound (usually administeredorally as a ball-milled suspension in 0.5% polysorbate) to inhibit thegrowth of xenografts of the human vulval epidermoid carcinoma cell lineA-431.

A-431 cells were maintained in culture in DMEM supplemented with 5% FCSand 2 mM glutamine. Freshly cultured cells were harvested bytrypsinization and injected subcutaneously (10 million cells/0.1ml/mouse) into both flanks of a number of donor nude mice. Whensufficient tumour material was available (after approximately 9 to 14days), fragments of tumour tissue were transplanted into the flanks ofrecipient nude mice (test day 0). Generally, on the seventh day aftertransplantation (test day 7) groups of 7 to 10 mice with similar-sizedtumours were selected and dosing of the test compound was commenced.Once-daily dosing of test compound was continued for a total of 13 days(test days 7 to 19 inclusive). In some studies the dosing of the testcompound was continued beyond test day 19, for example to test day 26.In each case, on the following day the animals were killed and finaltumour volume was calculated from measurements of the length and widthof the tumours. Results were calculated as a percentage inhibition oftumour volume relative to untreated controls.

Although the pharmacological properties of the compounds of the formulaI vary with structural change as expected, in general activity possessedby compounds of the formula I may be demonstrated at the followingconcentrations or doses in one or more of the above tests (a), (b), (c)and (d):

Test (a): IC₅₀ in the range, for example, 0.01-1 μM;

Test (b): IC₅₀ in the range, for example, 0.1-10 μM;

Test (c): ED₅₀ in the range, for example, 1-100 mg/kg;

Test (d): 20 to 70% inhibition of tumour volume from a daily dose in therange, for example, 50 to 400 mg/kg.

Thus, by way of example, the compound4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazolinehas an IC₅₀ of 0.04 μM in Test (a), an IC₅₀ of 0.19 μM in Test (b) andgives 64% inhibition in Test (d) at a dosage of 50 mg/kglday.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a quinazoline derivative ofthe formula I, or a pharmaceutically-acceptable salt thereof, as definedhereinbefore in association with a pharmaceutically-acceptable diluentor carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The quinazoline derivative will normally be administered to awarm-blooded animal at a unit dose within the range 5-5000 mg per squaremeter body area of the animal, i.e. approximately 0.1-100 mg/kg, andthis normally provides a therapeutically-effective dose. A unit doseform such as a tablet or capsule will usually contain, for example 1-250mg of active ingredient. Preferably a daily dose in the range of 1-100mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

According to a further aspect of the present invention there is provideda quinazoline derivative of the formula I as defined hereinbefore foruse in a method of treatment of the human or animal body by therapy.

We have now found that the compounds of the present invention possessanti-proliferative properties which are believed to arise from theirClass I (EGF type) receptor tyrosine kinase inhibitory activity.Accordingly the compounds of the present invention are expected to beuseful in the treatment of diseases or medical conditions mediated aloneor in part by Class I receptor tyrosine kinase enzymes, i.e. thecompounds may be used to produce a Class I receptor tyrosine kinaseinhibitory effect in a warm-blooded animal in need of such treatment.Thus the compounds of the present invention provide a method fortreating the proliferation of malignant cells characterised byinhibition of Class I receptor tyrosine kinase enzymes, i.e. thecompounds may be used to produce an anti-proliferative effect mediatedalone or in part by the inhibition of Class I receptor tyrosine kinase.Accordingly the compounds of the present invention are expected to beuseful in the treatment of cancer by providing an anti-proliferativeeffect, particularly in the treatment of Class I receptor tyrosinekinase sensitive cancers such as cancers of the by lung, colon, rectum,stomach. prostate, bladder, pancreas and ovary. The compounds of thepresent invention are also expected to be useful in the treatment ofother cell-proliferation diseases such as psoriasis, benign prostatichypertrophy, atherosclerosis and restenosis.

Thus according to this aspect of the invention there is provided the useof a quinazoline derivative of the formula I, or apharmaceutically-acceptable salt thereof, as defined hereinbefore in themanufacture of a medicament for use in the production of ananti-proliferative effect in a warm-blooded animal such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an anti-proliferative effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of aquinazoline derivative as defined immediately above.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular cell-proliferation disease willnecessarily be varied depending on the host treated, the route ofadministration and the severity of the illness being treated. A unitdose in the range, for example, 1-100 mg/kg, preferably 1-50 mg/kg isenvisaged.

The anti-proliferative treatment defined hereinbefore may be applied asa sole therapy or may involve, in addition to the quinazoline derivativeof the invention, conventional radiotherapy or one or more otheranti-tumour substances, for example cytotoxic or cytostatic anti-tumoursubstances, for example those selected from, for example, mitoticinhibitors, for example vinblastine, vindesine and vinorelbine;alkylating agents, for example cis-platin, carboplatin andcyclophosphamide; antimetabolites, for example 5-fluorouracil, tegafur,methotrexate, cytosine arabinoside and hydroxyurea, or, for example, oneof the preferred antimetabolites disclosed in European PatentApplication No. 239362 such asN-{5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl}-L-glutamicacid; intercalating antibiotics, for example adriamycin, mitomycin andbleomycin; enzymes, for example asparaginase; topoisomerase inhibitors,for example etoposide and camptothecin; biological response modifiers,for example interferon; and anti-hormones, for example antioestrogenssuch as tamoxifen, for example antiandrogens such as4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilideor, for example LHRH antagonists or LHRH agonists such as goserelin,leuprorelin or buserelin and hormone synthesis inhibitors, for examplearomatase inhibitors such as those disclosed in European PatentApplication No. 0296749, for example2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropionitrile),and, for example, inhibitors of 5α-reductase such as17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-en-3-one. Such conjointtreatment may be achieved by way of the simultaneous, sequential orseparate dosing of the individual components of the treatment. Accordingto this aspect of the invention there is provided a pharmaceuticalproduct comprising a quinazoline derivative of the formula I as definedhereinbefore and an additional anti-tumour substance as definedhereinbefore for the conjoint treatment of cancer.

As stated above the quinazoline derivative defined in the presentinvention is an effective anti-cancer agent, which property is believedto arise from its Class I (EGF type) receptor tyrosine kinase inhibitoryproperties. Such a quinazoline derivative of the invention is expectedto possess a wide range of anti-cancer properties as Class I receptortyrosine kinases have been implicated in many common human cancers suchas leukaemia and breast, lung, colon, rectal, stomach, prostate,bladder, pancreas and ovarian cancer. Thus it is expected that aquinazoline derivative of the invention will possess anti-canceractivity against these cancers. It is in addition expected that aquinazoline derivative of the present invention will possess activityagainst a range of leukaemias, lymphoid malignancies and solid tumourssuch as carcinomas and sarcomas in tissues such as the liver, kidney,prostate and pancreas.

It is further expected that a quinazoline derivative of the presentinvention will possess activity against other cell-proliferationdiseases such as psoriasis, benign prostatic hypertrophy,atherosclerosis and restenosis.

It is also to be expected that a quinazoline derivative of the inventionwill be useful in the treatment of additional disorders of cellulargrowth in which aberrant cell signalling by way of receptor tyrosinekinase enzymes, including as yet unidentified receptor tyrosine kinaseenzymes, are involved. Such disorders include,for example, inflammation,angiogenesis, vascular restenosis, immunological disorders,pancreatitis, kidney disease and blastocyte maturation and implantation.

The invention will now be illustrated in the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon;

(iii) column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were performed on Merck Kieselgel silica(Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silicaobtained from E. Merck, Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) melting points were determined using a Mettler SP62 automaticmelting point apparatus, an oil-bath apparatus or a Koffler hot plateapparatus.

(vi) the structures of the end-products of the formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multilicities are shown as follows:s, singlet; d, doublet; t, triplet; m, multiplet, unless otherwisestated end-products of the formula I were dissolved in CD₃SOCD₃ for thedetermination of NMR values.

(vii) intermediates were not generally fully characterised and puritywas assessed by thin layer chromatography (TLC), infra-red (IR) or NMRanalysis;

(viii) the following abbreviations have been used:

DMF N,N-dimethylformamide;

DMA N,N-dimethylacetamide;

NMP N-methylpyrrolidin-2-one;

THF tetrahydrofuran;

DME 1,2-dimethoxyethane.

EXAMPLE 1

Tetrakis(triphenylphosphine)palladium(0) (0.04 g) was added to a stirredmixture of 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloridesalt (0.25 g), a saturated aqueous sodium bicarbonate solution (1.5 ml),di-isopropyl 4-cyanophenylboronate and DME (10 ml). The resultantmixture was stirred and heated to reflux for 3 hours. The mixture wascooled to ambient temperature. An aqueous sodium hydroxide solution (5M,2 ml) and water were added in turn and the resultant precipitate wasisolated by filtration, dried and purified by column chromatographyusing a 10:1 mixture of methylene chloride and methanol as eluent. Therewas thus obtained4-(3-chloro-4-fluoroanilino)-6-(4-cyanophenyl)quinazoline (0.05 g, 18%),m.p. >250° C.; NMR Spectrum: 7.5 (t, 1H), 7.85 (m, 1H), 7.9 (d, 1H),8.0-8.15 (m, 4H), 8.2 (m, 1H), 8.55 (m, 1H), 8.65 (s, 1H), 8.9 (d, 1H),10.0 (broad s, 1H); Elemental Analysis: Found C, 66.1; H, 3.3; N, 14.3;C₂₁H₁₂ClFN₄ 0.35H₂O requires C, 66.2; H, 3.4; N, 14.7%.

The 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride saltused as a starting material was obtained as follows:

A mixture of 5-bromoanthranilic acid (15.2 g) and formamide (20 ml) washeated to 140° C. for 2 hours and then to 190° C. for 2 hours. Themixture was cooled to ambient temperature. Methanol (20 ml) was addedand the mixture was heated to reflux for 5 minutes. Water (150 ml) wasadded and the mixture was cooled to ambient temperature. The precipitatewas washed with water and dried. There was thus obtained6-bromo-3,4-dihydroquinazolin-4-one (14.1 g).

A mixture of a portion (2.85 g) of the material so obtained, thionylchloride (30 ml) and DMF (4 drops) was stirred and heated to reflux for3 hours. The mixture was evaporated to give 6-bromo-4-chloroquinazolinewhich was used without further purification.

A mixture of the material so obtained, 3-chloro-4-fluoroaniline (1.85 g)and isopropanol (30 ml) was stirred and heated to reflux for 3 hours.The mixture was allowed to cool to ambient temperature and the solid wasisolated, washed in turn with isopropanol and diethyl ether and dried.There was thus obtained 6-bromo-4-(3-chloro-4-fluoroanilino)quinazolinehydrochloride salt, (2.65 g); NMR Spectrum: 7.53 (t, 1H), 7.8 (m, 1H),7.94 (d, 1H), 8.09 (m, 1H), 8.26 (m, 1H), 8.98 (s, 1H), 9.3 (d, 1H);Elemental Analysis: Found C, 43.2, H, 2.4; N, 10.6; C₁₄H₈BrClFN₃ 1HClrequires C, 43.2; H, 2.3; N, 10.8%.

The di-isopropyl 4-cyanophenylboronate used as a starting material wasobtained as follows:

n-Butyllithium (1.6M in hexane, 1 ml) was added dropwise to a stirredmixture of 4-bromobenzonitrile (0.254 g), tri-isopropyl borate (0.4 ml)and THF (10 ml) which had been coiled to −78° C. The resultant mixturewas stirred and allowed to warm to ambient temperature. The mixture wasevaporated to give the required starting material which was used withoutfurther purification.

EXAMPLE 2

Tetrakis(triphenylphosphine)palladium(0) (0.019 g) and a solution ofphenylboronic acid (0.083 g) in ethanol (1 ml) were added in turn to astirred mixture of 6-bromo-4-(3-methylanilino)quinazoline hydrochloridesalt (European Patent Application No. 0520722, Example 9 thereof, 0.245g), a saturated aqueous sodium carbonate solution (0.4 ml) and toluene(1.2 ml). The resultant mixture was stirred and heated to reflux for 6hours. The mixture was cooled to ambient temperature and partitionedbetween methylene chloride and water. The organic phase was washed withwater, dried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 4:1 mixture of methylene chloride and ethylacetate as eluent. There was thus obtained4-(3-methylanilino)-6-phenylquinazoline 0.159 g), m.p. 207-209° C.; NMRSpectrum: 2.3 (s, 3H), 6.95 (d, 1H), 7.3 (t, 1H), 7.4-7.9 (m, 8H), 8.2(m, 1H), 8.6 (s, 1H), 8.85 (m, 1H), 9.8 (broad s, 1H); ElementalAnalysis: Found C, 78.8; H, 5.5; N, 12.7; C₂₁H₁₇N₃ 0.5H₂ requires C,78.7; H, 5.6; N, 13.1%.

EXAMPLE 3

Lithium aluminium hydride (1M in diethyl ether, 20 ml) was addeddropwise to a stirred mixture of4-(3-chloro-4-fluoroanilino)-6-(4-cyanophenyl)quinazoline (0.706 g),diethyl ether (25 ml) and THF (25 ml) and the resultant mixture wasstirred at ambient temperature for 16 hours. The mixture was cooled to0° C. Water (2 ml), 5M aqueous sodium hydroxide solution (2 ml) andwater (6 ml) were added in turn and the mixture was allowed to warm toambient temperature. The mixture was filtered and the filtrate wasevaporated. The residue was purified by column chromatography using a10:1 mixture of methylene chloride and methanol as eluent. There wasthus obtained6-(4-aminomethylphenyl)-4-(3-chloro-4-fluoroanilino)quinazoline (0.409g); NMR Spectrum: 4.0 (s, 2H), 7.4 (t, 1H), 7.6 (d, 2H), 7.8-8.0 (m,4H), 8.2 (m, 2H), 8.6 (s, 1H), 8.9 (s, 1H), 10.1 (broad s, 1H).

EXAMPLE 4

Tetrakis(triphenylphosphine)palladium(0) (0.05 g) and a saturatedaqueous sodium bicarbonate solution (5 ml) were added in turn to astirred mixture of 6-bromo-4-(3-chloro-4-fluoroanilino)quinazolinehydrochloride salt (0.35 g), 3-furylboronic acid (J. Het. Chem., 1975,195; 0.208 g) and DME (15 ml). The resultant mixture was stirred andheated to reflux for 2 hours. The mixture was cooled to ambienttemperature and partitioned between ethyl acetate and water. The organicphase was washed with water and with brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography usinginitially methylene chloride and then increasingly polar mixtures ofmethylene chloride and methanol as eluent. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(3-furyl)quinazoline; NMR Spectrum: 7.16(m, 1H), 7.48 (t, 1H), 7.82 (d, 1H), 7.85 (m, 2H), 8.16 (m, 1H), 8.18(m, 1H), 8.35 (d, 1H), 8.61 (s, 1H), 8.7 (d, 1H), 9.88 (s, 1H);Elemental Analysis: Found C, 62.8; H, 3.4; N, 10.8; C₁₈H₁₁ClFN₃O 0.25H₂Orequires C, 62.8; H, 3.3; N, 12.2%.

EXAMPLE 5

Tetrakis(triphenylphosphine)palladium(0) (0.05 g) was added to a stirredmixture of 6-bromo4-(3-chloro-4-fluoroanilino)quinazoline hydrochloridesalt (0.613 g), a saturated aqueous sodium bicarbonate solution (10 ml),di-isopropyl 2-furylboronate and DME (20 ml). The resultant mixture wasstirred and heated to reflux for 1.5 hours. The mixture was cooled toambient temperature. An aqueous sodium hydroxide solution (5M, 10 ml)and water were added in turn. The resultant precipitate was isolated,washed with a small amount of methylene chloride and dried. There wasthus obtained 4-(3-chloro-4-fluoroanilino)-6-(2-furyl)quinazoline (0.54g), m.p. 232-234° C.; NMR Spectrum: 6.7 (m, 1H), 7.15 (d, 1H), 7.4 (t,1H), 7.8 (m, 3H), 8.2 (m, 2H), 8.55 (s, 1H), 8.8 (d, 1H), 10.0 (broad s,1H); Elemental Analysis: Found C, 57.8; H, 3.6; N, 10.9; C₁₈H₁₁ClFN₃O1.9H₂O requires C, 57.8; H, 4.0; N, 11.2%.

The di-isopropyl 2-furylboronate used as a starting material wasobtained as follows:

n-Butyllithium (1.6M in hexane, 2.75 ml) was added dropwise to a stirredsolution of furan (0.25 g) in THF (10 ml) which had been cooled to 0° C.The resultant mixture was stirred at ambient temperature for 20 minutes.The mixture was cooled to −78° C. and triisopropyl borate (1 ml) wasadded dropwise. The mixture was allowed to warm to ambient temperatureand was stirred for 2 hours. The mixture was evaporated to give therequired starting material which was used without further purification.

EXAMPLE 6

Using an analogous procedure to that described in Example 5 except thatthe reaction mixture was heated to reflux for 3 hours,6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt wasreacted with di-isopropyl 2-thienylboronate to give4-(3-chloro-4-fluoroanilino)-6-(2-thienyl)quinazoline in 36% yield, m.p.205-208° C.; NMR Spectrum: 7.2 (m, 1H), 7.4 (t, 1H), 7.7 (m, 2H), 7.8(m, 2H), 8.15 (m, 2H), 8.55 (s, 1H), 8.75 (d, 1H), 10.0 (broad s, 1H);Elemental Analysis: Found C, 58.6; H, 3.1; N, 11.3; C₁₈H₁₁ClFN₃S 0.75H₂Orequires C, 53.5; H, 3.4; N, 11.4%.

The di-isopropyl 2-thienylboronate used as a starting material wasobtained as follows:

n-Butyllithium (1.6M in hexane, 2 ml) was added dropwise to a stirredsolution of 2-bromothiophene (0.515 g) in THF (6 ml) which had beencooled to −78° C. Tri-isopropyl borate (0.75 ml) was added dropwise andthe resultant mixture was stirred and allowed to warm to ambienttemperature. The mixture was evaporated to give the required startingmaterial which was used without further purification.

EXAMPLE 7

Using an analogous procedure to that described in Example 5 except thatthe reaction mixture was heated to reflux for 2 hours,6-bromo4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt wasreacted with di-isopropyl 3-thienylboronate to give4-(3-chloro-4-fluoroanilino)-6-(3-thienyl)quinazoline in 51% yield, m.p.195-197° C.; NMR Spectrum: 7.5 (t, 1H), 7.7-7.9 (m, 4H), 8.05 (m, 1H),8.2 (m, 1H), 8.25 (m, 1H), 8.6 (s, 1H), 8.8 (d, 1H), 9.9 (broad s, 1H);Elemental Analysis: Found C, 57.8; H, 3.3; N, 10.6; C₁₈H₁₁ClFN₃S 1.15H₂Orequires C, 57.4; H, 3.6; N, 11.2%.

The di-isopropyl 3-thienylboronate used as a starting material wasobtained by the reaction of 3-bromothiophene and tri-isopropyl borateusing an analogous procedure to that described in the portion of Example6 which is concerned with the preparation of starting materials.

EXAMPLE 8

Using an analogous procedure to that described in Example 5 except thatthe reaction mixture was heated to reflux for 4 hours,6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt wasreacted with di-isopropyl 5-(2-morpholinoethyl)thien-2-ylboronate. Thereaction mixture was cooled to ambient temperature and partitionedbetween methylene chloride and water. The organic phase was washed withbrine, dried (MgSO₄) and evaporated. The residue was triturated under amixture of hexane and ethyl acetate to give4-(3-chloro-4-fluoroanilino)-6-[5-(2-morpholinoethyl)thien-2-yl]quinazolinein 27% yield; NMR Spectrum: 2.6-2.7 (t, 2H), 3.0 (t, 2H), 3.65 (t, 4H),7.0 (d, 1H), 7.45 (t, 1H), 7.55 (d, 1H), 7.8 (m, 2H), 8.1 (m, 1H), 8.2(m, 1H), 8.6 (s, 1H), 8.75 (d, 1H), 9.95 (broad s, 1H); ElementalAnalysis: Found C, 59.0; H, 4.9; N, 11.3; C₂₄H₂₂ClFN₄OS 1H₂O requires C,59.2; H, 5.0; N, 11.5%.

The di-isopropyl 5-(2-morpholinoethyl)thien-2-ylboronate used as astarting material was obtained as follows:

2-(2-Thienyl)acetyl chloride (16 g) was added slowly to a stirredmixture of morpholine (17.5 ml) and methylene chloride (150 ml). Afurther portion (5 ml) of morpholine was added and the mixture wasstirred at ambient temperature for 4 hours. The reaction mixture waswashed in turn with 2M aqueous hydrochloric acid, a saturated aqueoussodium bicarbonate solution and brine. The organic phase was dried andevaporated. The residue was triturated under a mixture of hexane anddiethyl ether to give N-[2-(2-thienyl)acetyl]morpholine (20.9 g).

Lithium aluminium hydride (1M in diethyl ether, 28.3 ml) was addedslowly to a stirred solution of N-[2-(2-thienyl)acetyl]morpholine (3 g)in THF (100 ml). The resultant mixture was heated to 45° C. for 30minutes. A 2M aqueous hydrochloric acid solution was added dropwise todestroy the excess of reducing agent and the mixture was partitionedbetween methylene chloride and a 2M aqueous sodium hydroxide solution.The organic phase was washed with brine, dried (MgSO₄) and evaporated togive 2-(2-morpholinoethyl)thiophene (1.7 g).

A portion (1.22 g) of the material so obtained was dissolved in THF (75ml) and the solution was cooled to −78° C. n-Butyllithium (1.6M inhexane, 3.86 ml) was added dropwise and the mixture was stirred at −78°C. for 30 minutes. A solution of tri-isopropyl borate (1.16 ml) in THF(25 ml) was added and the reaction mixture was then allowed to warm toambient temperature. The mixture was evaporated to give di-isopropyl5-(2-morpholinoethyl)thien-2-ylboronate which was used without furtherpurification.

EXAMPLE 9

Using an analogous procedure to that described in Example 5 except thatthe reaction mixture was heated to reflux for 2 hours,6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt wasreacted with di-isopropyl 5-morpholinomethylthien-3-ylboronate. Thereaction mixture was cooled to ambient temperature and partitionedbetween methylene chloride and water. The organic phase was washed withbrine, dried and evaporated. The residue was purified by columnchromatography using a 25:1 mixture of methylene chloride and methanolas eluent. The resultant product was recrystallised from ethyl acetate.There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(5-morpholinomethylthien-3-yl)quinazolinein 30% yield; NMR Spectrum: 2.5 (t, 4H), 3.6 (t, 4H), 3.75 (s, 2H), 7.45(t, 1H), 7.6 (d, 1H), 7.8 (m, 2H), 7.95 (d, 1H), 8.22 (m, 2H), 8.6 (s,1H), 8.75 (d, 1H), 9.9 (broad S, 1H); Elemental Analysis: Found C, 58.5;H, 4.8; N, 11.7; C₂₃H₂₀ClFN₄OS 1H₂O requires C, 58.4; H, 4.7; N, 11.8%.

The di-isopropyl 5-morpholinomethylthien-3-ylboronate used as a startingmaterial was obtained as follows:

Sodium cyanoborohydride (2 g) was added portionwise to a stirred mixtureof 4-bromo-2-thiophenecarbaldehyde (4.78 g), morpholine (2.1 g), glacialacetic acid (1.8 g) and ethanol (125 ml). The mixture was stirred atambient temperature for 1 hour. The mixture was poured into a saturatedaqueous sodium bicarbonate solution and extracted with methylenechloride. The organic phase was washed with brine and evaporated. Theresultant oil was partitioned between a dilute (10%) aqueoushydrochloric acid solution and methylene chloride. The aqueous phase wasbasified by the addition of a saturated aqueous sodium bicarbonatesolution and extracted with methylene chloride. The organic extract wasdried (MgSO₄) and evaporated to give 4-bromo-2-morpholinomethylthiophene(3.2 g); NMR Spectrum: 2.4 (t, 4H), 3.55 (t, 4H), 3.65 (s, 2H), 6.95 (d,1H), 7.5 (d, 1H).

A portion (1.22 g) of the material so obtained was dissolved in THF (100ml) and the solution was cooled to −78° C. Tri-isopropyl borate (0.963g) and n-butyllithium (1.6M in hexane, 2.91 ml) were added in turn. Themixture was stirred at −78° C. for 30 minutes and then allowed to warmto ambient temperature. The mixture was evaporated to give diisopropyl5-morpholinomethylthien-3-ylboronate which was used without furtherpurification.

EXAMPLE 10

A mixture of 6-(2-chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline(0.5 g) and formamide (2 ml) was stirred and heated to 140° C. for 2hours. The mixture was cooled to ambient temperature and water wasadded. The precipitate was isolated and purified by columnchromatography on a C18 reversed-phase silica column using decreasinglypolar mixtures of water and methanol (containing 0.2% of trifluoroaceticacid) as eluent. There were thus obtained in turn:

4-(3-chloro-4-fluoroanilino)-6-(4-imidazolyl)quinazoline (0.135 g); NMRSpectrum: 7.54 (t, 1H), 7.78 (m, 1H), 7.94 (d, 1H), 8.07 (d, 1H), 8.12(m, 1H), 8.38 (m, 1H), 8.81 (s, 1H), 8.82 (s, 1H), 9.01 (s, 1H);Elemental Analysis: Found C, 42.9; H, 2.5; N, 11.4; C₁₇H₁₁ClFN₅ 1.4H₂O2CF₃CO₂H requires C, 42.5; H, 2.7; N, 11.8%; and4-(3-chloro-4-fluoroanilino)-6-(4-oxazolyl)quinazoline (0.056 g); NMRSpectrum: 7.53 (t, 1H), 7.8 (m, 1H), 7.93 (d, 1H), 8.12 (m, 1H), 8.42(m, 1H), 8.65 (s, 1H), 8.8 (s, 1H), 8.88 (s, 1H), 9.1 (d, 1H); ElementalAnalysis: Found C. 47.0; H. 2.3; N, 11.2; C₁₇H₁₁ClFN₄O 1.5CF₃CO₂Hrequires C. 46.9; H, 2.3; N, 10.9%.

The 6-(2-chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline used as astarting material was obtained as follows:

Triphenylphosphine (0.063 g) was added to a stirred mixture of6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline hydrochloride salt (2.34g), triethylamine (3.4 ml), (trimethylsilyl)acetylene (1.33 ml)palladium(II) chloride (0.021 g), cuprous iodide (0.045 g) and DMF (15ml). The mixture was stirred and heated to 90° C. for 2 hours. Themixture was evaporated and the residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(2-trimethylsilylethynyl)quinazoline (2.2g).

A mixture of a portion (2 g) of the material so obtained, potassiumcarbonate (0.25 g) and methanol (100 ml) was stirred at ambienttemperature for 2 hours. The mixture was acidified to pH5 by theaddition of glacial acetic acid. The resultant mixture was evaporatedand the residue was partitioned between methylene chloride and water.The organic phase was dried (MgSO₄) and evaporated. There was thusobtained 4-(3-chloro-4-fluoroanilino)-6-ethynylquinazoline (1.68 g),m.p. 224-226° C.; NMR Spectrum: 4.42 (s, 1H), 7.45 (t, 1H), 7.59 (d,1H), 7.8-7.93 (m, 2H), 8.23 (m, 1H), 8.65 (s, 1H), 8.77 (s, 1H), 9.8(broad s, 1H).

A mixture of a portion (1.2 g) of the material so obtained, mercurictrifluoroacetate (0.1 g), water (1 ml) and trifluoroacetic acid (15 ml)was stirred and heated to reflux for 4 hours. The mixture was evaporatedand the residue was purified by column chromatography using increasinglypolar mixtures of methylene chloride and methanol as eluent. Thematerial so obtained was triturated under methylene chloride. There wasthus obtained 6-acetyl-4-(3-chloro-4-fluoroanilino)quinazoline (0.37 g),m.p. 211-213° C.; NMR Spectrum: 2.75 (s, 3H), 7.47 (t, 1H), 7.83 (m,1H), 7.88 (d, 1H), 8.14 (m, 1H), 8.33 (m, 1H), 8.69 (s, 1H), 9.19 (d,1H).

Chlorine gas was led into a stirred mixture of6-acetyl-4-(3-chloro-4-fluoroanilino)quinazoline (0.11 g), methylenechloride (40 ml) and ethanol (60 ml) and the mixture was cooled to atemperature in the range 20 to 25° C. After 10 minutes the supply ofchlorine was stopped and the reaction mixture was stirred at ambienttemperature for 1 hour. The mixture was evaporated to give6-(2chloroacetyl)-4-(3-chloro-4-fluoroanilino)quinazoline (0.114 g)which was used without further purification.

EXAMPLE 11

A mixture of 6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline (0.5 g),2-pyridyl-tri-n-butyltin (J. Het. Chem., 1990, 2165; 0.8 g),tetrakis(triphenylphosphine)palladium(0) (0.05 g) and THF (20 ml) wasstirred and heated to 60° C. for 4 days. The mixture was evaporated andthe residue was purified by column chromatography using initiallymethylene chloride and then increasingly polar mixtures of methylenechloride and methanol as eluent. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(2-pyridyl)quinazoline (0.11 g); NMRSpectrum: 7.45 (m, 1H), 7.47 (t, 1H), 7.88 (m, 1H), 7.9 (d, 1H), 8.03(m, 1H), 8.18 (d, 1H), 8.22 (d, 1H), 8.63 (m, 1H), 8.66 (s, 1H), 8.75(m, 1H), 9.19 (d, 1H); Elemental Analysis: Found C, 61.5; H, 3.6; N,14.9; C₁₉H₁₂ClFN₄ 1.1H₂O requires C, 61.6; H, 3.8; N, 15.1%.

EXAMPLE 12

Diethyl-3-pyridylborane (0.176 g) was added to a mixture of6-bromo-4-(3-chloro-4-fluoroanilino)quinazoline (0.53 g), powderedpotassium hydroxide (0.202 g), tetra-n-butylammonium bromide (0.042 g),tetrakis(triphenylphosphine)palladium(0) (0.069 g) and THF (10 ml). Theresultant mixture was stirred and heated to reflux for 16 hours. Themixture was evaporated and the residue was purified by columnchromatography using initially methylene chloride and then increasinglypolar mixtures of methylene chloride and methanol as eluent. There wasthus obtained 4-(3-chloro-4-fluoroanilino)-6-(3-pyridyl)quinazoline(0.125 g); NMR Spectrum: 7.5 (t, 1H), 7.6 (m, 1H), 7.88 (m, 1H), 7.93(d, 1H), 8.2 (m, 1H), 8.28 (m, 1H), 8.3 (m, 1H), 8.68 (m, 2H), 8.91 (d,1H), 9.16 (d, 1H), 10.02 (broad s, 1H); Elemental Analysis: Found C,64.3; H, 3.3; N, 15.6; C₁₉H₁₂ClFN₄ 0.25H₂O requires C, 64.2; H, 3.5; N,15.8%.

EXAMPLE 13

A mixture of 6-amino4-(3-chloro-4-fluoroanilino)quinazoline (0.576 g),4-chloroquinazoline hydrochloride salt (0.83 g) and isopropanol (10 ml)was stirred and heated to reflux for 5 hours. The hot reaction mixturewas filtered and the filtrate was allowed to cool to ambienttemperature. The resultant solid was isolated, washed with isopropanoland with diethyl ether and dried. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(4-quinazoline dihydrochloride salt (0.86g); NMR Spectrum: 7.54 (t, 1H), 7.8 (m, 1H), 7.92 (t, 1H), 8.0-8.2 (m,4H), 8.38 (m, 1H), 8.97 (s, 1H), 8.98 (s, 1H), 9.06 (d, 1H), 9.28 (d,1H), 11.75 (broad s, 1H), 12.26 (broad s, 1H); Elemental Analysis: FoundC, 53.4; H, 3.4; N, 16.9; C₂₂H₁₄ClFN₆ 2HCl 0.33H₂O requires C, 53.2; H,3.4; N, 16.9%.

The 6-amino-4-(3-chloro-4-fluoroanilino)quinazoline used as a startingmaterial was obtained as follows:

3-Chloro-4-fluoroaniline (3.6 g) was added to a stirred mixture of4-chloro-6-nitroquinazoline (European Patent Application No. 0566226,Example 8 thereof; 5 g); THF (10 ml) and DMF (10 ml). The resultantmixture was stirred at ambient temperature for 5 hours. The precipitatewas isolated and partitioned between water and a 9:1 mixture ofmethylene chloride and methanol. The aqueous phase was neutralised bythe addition of a saturated aqueous sodium bicarbonate solution andre-extracted with methylene chloride. The organic phases were combinedand evaporated. The residue was triturated under a 9:1 mixture ofethanol and water. The resultant solid was isolated and dried. There wasthus obtained 4-(3-chloro-4-fluoroanilino)-6-nitroquinazoline (2.5 g).

A mixture of a portion (2.3 g) of the material so obtained, 10%palladium-on-carbon catalyst (0.4 g), ethanol (25 ml) and DMF (25 ml)was stirred under an atmosphere of hydrogen for 2 hours. The mixture wasfiltered and the filtrate was evaporated. The residue was trituratedunder a 4:1 mixture of ethanol and water. The resultant solid wasisolated and dried. There was thus obtained6-amino-4-(3-chloro-4-fluoroanilino)quinazoline (0.35 g, 17%); NMRSpectrum: 5.6 (broad s, 2H), 7.27 (m, 1H), 7.32 (s, 1H), 7.41 (t, 1H),7.55 (d, 1H), 7.8 (m, 1H), 8.19 (m, 1H), 8.38 (s, 1H), 9.53 (broad s,1H); Elemental Analysis: Found C, 58.1; H, 3.6; N, 19.0; C₁₄H₁₀ClFN₄requires C, 58.2; H, 3.5; N, 19.4%.

EXAMPLE 14

A mixture of 6-amino-4-(3-methylanilino)quinazoline (European PatentApplication No. 0566226, Example 8 thereof; 0.2 g), 2-fluoroimidazole4-toluenesulphonic acid salt (0.2 g), 4-toluenesulphonic acid (0.26 g)and DMF (1 ml) was stirred and heated to 100° C. for 16 hours. Themixture was cooled to ambient temperature and partitioned betweenmethylene chloride and a saturated aqueous sodium bicarbonate solution.The organic phase was dried (MgSO₄) and evaporated and the residue waspurified by column chromatography using a 9:1 mixture of methylenechloride and methanol as eluent. There was thus obtained6-(2-imidazolylamino)-4-(3-methylanilino)quinazoline (0.09 g), m.p.256-258° C.; NMR Spectrum: 2.33 (s, 3H), 6.77 (d, 2H), 6.95 (d, 1H),7.24 (t, 1H), 7.6 (m, 3H), 7.85 (m, 1H), 8.11 (m, 1H), 8.39 (s, 1H),8.94 (s, 1H), 9.4 (s, 1H), 11.0 (s, 1H); Elemental Analysis: Found C,68.1; H, 5.3; N, 26.4; C₁₈H₁₆N₆ requires C, 68.3; H, 5.1; N, 26.6%.

The 2-fluoroimidazole 4-toluenesulphonic acid salt used as a startingmaterial was obtained from 2-aminoimidazole using analogous proceduresto those described in J. Het. Chem., 1978, 1227 and J. Amer. Chem. Soc.,1973, 4619.

EXAMPLE 15

1-Methylimidazole-4-sulphonyl chloride (0.181 g) was added to a stirredmixture of 6-amino-4-(3-methylanilino)quinazoline (0.25 g) and pyridine(10 ml) and the mixture was stirred at ambient temperature for 16 hours.The mixture was evaporated and the residual oily solid was washed withmethylene chloride and with a saturated aqueous sodium bicarbonatesolution. The solid was then washed with water and with acetone anddried. There was thus obtained4-(3-methylanilino)-6-(1-methylimidazole4-sulphonamido)quinazoline (0.07g), m.p. >250° C.; NMR Spectrum: (CD₃SOCD₃+CD₃CO₂D) 2.37 (s, 3H), 3.64(s, 3H), 6.98 (d, 1H), 7.27 (t, 1H), 7.5-7.8 (m, 6H), 8.2 (d, 1H), 8.48(s, 1H); Elemental Analysis: Found C, 54.7; H, 4.4; N, 19.7; C₁₉H₁₈N₆O₂S1.2H₂O requires C, 54.8; H1 4.9; N, 20.2%.

EXAMPLE 16

Sodium cyanoborohydride (0.126 g) was added portionwise to a stirredmixture of 6-amino-4(3-methylanilino quinazoline (0.25 g),3-thiophenecarbaldehyde (0.26 ml), glacial acetic acid (0.114 ml) andethanol (20 ml). The resultant mixture was stirred at ambienttemperature for 16 hours. The mixture was basified by the addition of asaturated aqueous sodium bicarbonate solution and evaporated. Theresidue was washed with water and dried. There was thus obtained4-(3-methylanilino)-6-(3-thienylmethylamino)quinazoline (0.335 g), m.p.207-208° C.; NMR Spectrum: 2.3 (s, 3H), 4.45 (d, 2H), 6.52 (d, 1H), 6.9(t, 1H), 7.2 (m, 1H), 7.3 (m, 3H), 7.5 (m, 3H), 7.65 (m, 2H), 8.3 (s,1H), 9.2 (broad s, 1H); Elemental Analysis: Found C, 68.6; H, 5.2; N,15.3; C₂₀H₁₈N₄S 0.3H₂O requires C, 68.3; H, 5.3; N, 15.9%.

EXAMPLE 17

Sodium cyanoborohydride (0.126 g) was added portionwise to a stirredmixture of 6-amino-4-(3-methylanilino)quinazoline (0.25 g),2-imidazolecarbaldehyde (0.192 g), glacial acetic acid (0.114 ml) andethanol (20 ml). The resultant mixture was stirred at ambienttemperature for 3 hours. The mixture was basified by the addition of asaturated aqueous sodium bicarbonate solution and evaporated. Theresidue was washed with water and dried. There was thus obtained6-(2-imidazolylmethylamino)-4-(3-methylanilino)quinazoline (0.096 g),m.p. 235-237° C.; NMR Spectrum: (CD₃SOCD₃+CD₃CO₂D, 100° C.) 2.3 (s, 3H),4.45 (d, 2H), 6.5 (t, 1H), 6.9 (d, 1H), 7.1 (s, 2H), 7.3 (m, 3H), 7.5(d, 1H), 7.65 (m, 2H), 8.3 (s, 1H), 9.2 (s, 1H), 12.0 (s, 1H); ElementalAnalysis: Found C, 67.4; H, 5.3; N, 24.8; C₁₉H₁₈N₆ 0.5H₂O requires C,67.3; H, 5.6; N, 24.8%.

EXAMPLE 18

2-Thiophenecarbonyl chloride (0.6 g) was added portionwise to a stirredsolution of 6-amino-4-(3-chloro-4-fluoroanilino)quinazoline (1.04 g) inDMA (10 ml). The mixture was stirred at ambient temperature for 30minutes. Methylene chloride (25 ml) was added and the precipitate wasisolated and dried. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(thiophene-2-carboxamido)quinazolinehydrochloride salt (1.35 g), m.p. >250° C.; NMR Spectrum: 7.27 (m, 1H),7.54 (t, 1H), 7.7 (m, 1H), 7.9 (m, 1H), 8.0 (m, 2H), 8.28 (m, 2H), 8.9(s, 1H), 9.2 (d, 1H), 10.99 (s, 1H), 11.5 (broad s, 1H); ElementalAnalysis: Found C, 52.1; H, 3.3; N, 12.9; C₁₉H₁₂ClFN₄OS 1HCl 0.15DMArequires C, 52.5; H, 3.2; N, 13.0%.

EXAMPLE 19

Lithium aluminium hydride (1M in diethyl ether, 7.1 ml) was addeddropwise to a stirred mixture of4-(3-chloro-4-fluoroanilino)-6-(thiophene-2-carboxamido)quinazolinehydrochloride salt (1 g) and THF (200 ml). The mixture was stirred atambient temperature for 2 hours and then heated to 45° C. for 1 hour.The mixture was cooled to ambient temperature and glacial acetic acid (5ml) was added to destroy the excess of reducing agent. The mixture wasevaporated and the residue was partitioned between methylene chlorideand a 5M aqueous sodium hydroxide solution. The organic phase was washedwith brine, dried and evaporated. The residue was purified by columnchromatography using a 99:1 mixture of methylene chloride and methanolas eluent. The product so obtained as triturated under diethyl ether.There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(2-thienylmethylamino)quinazoline (0.095g), m.p. 193-195 ° C.; NMR Spectrum: 4.65 (d, 2H), 6.75 (t, 1H), 7.0 (m,1H), 7.4 (m, 4H), 7.55 (d, 1H), 7.8 (m, 1H), 8.15 (m, 1H), 8.4 (s, 1H),9.4 (broad s, 1H); Elemental Analysis: Found C, 59.3; H, 3.8; N, 14.0;C₁₉H₁₄ClFN₄S 0.1Et₂O requires C, 59.4; H, 3.85; N, 14.3%.

EXAMPLE 20

2-Furoyl chloride (0.287 g) was added portionwise to a stirred solutionof 6-amino-4-(3-chloro-4-fluoroanilino)quinazoline (0.577 g) in DMA (3ml) and the resultant mixture was stirred at ambient temperature for 18hours. The mixture was evaporated and the residue was purified by columnchromatography using increasingly polar mixtures of methylene chlorideand methanol as eluent. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(furan-2-carboxamido)quinazoline (0.436g); NMR Spectrum: 6.75 (m, 1H), 7.56 (m, 2H), 7.69 (m, 1H), 8.0 (m, 3H),8.27 (m, 1H), 8.91 (s, 1H), 9.13 (d, 1H), 10.85 (broad s, 1H), 11.5(broad s, 1H); Elemental Analysis: Found C, 54.3; H. 3.1; N, 13.3;C₁₉H₁₂ClFN₄O₂ requires C, 54.3; H, 3.1; N, 13.4%.

EXAMPLE 21

Using an analogous procedure to that described in Example 19,4-(3-chloro-4-fluoroanilino)-6-(furan-2-carboxamido)quinazoline wasreduced to give4-(3-chloro-4-fluoroanilino)-6-(2-furfurylamino)quinazoline in 16%yield, m.p. 197-199° C.; NMR Spectrum: 4.45 (d, 2H); 6.4 (m, 1H), 6.7(m, 1H), 7.3-7.6 (m, 5H), 7.8 (m, 1H), 8.15 (m, 1H), 8.4 (s, 1H), 9.5(m, 1H); Elemental Analysis: Found C, 59.8; H, 3.7; N, 14.5;C₁₉H₁₄ClFN₄O 0.2CH₂Cl₂ requires C, 59.8; H, 3.8; N, 14.5%.

EXAMPLE 22

Using an analogous procedure to that described in Example 18,6-amino-4-(3-chloro-4-fluoroanilino)quinazoline was reacted with5-isoxazolecarbonyl chloride to give4-(3-chloro-4-fluoroanilino)-6-(isoxazole-5-carboxamido)quinazolinehydrochloride salt in 87% yield, m.p. >250° C.; NMR Spectrum: 7.4 (d,1H), 7.5 (t, 1H), 7.65 (m, 2H), 8.0 (m, 2H), 8.85 (d, 1H), 8.9 (s, 1H),11.4 (s, 1H); Elemental Analysis: Found C, 50.8; H, 3.3; N, 16.3;C₁₈H₁₁ClFN₅O₂ 1HCl 0.4H₂O 0.24DMA requires C, 50.8; H, 3.4; N, 16.4%.

EXAMPLE 23

N,N′-Dicyclohexylcarbodiimide (0.416 g) was added portionwise to astirred mixture of 1,2,3-triazole4-carboxylic acid (0.226 g) and DMA (10ml). The resultant mixture was stirred at ambient temperature for 2hours. A solution of 6-amino-4-(3-chloro-4-fluoroanilino)quinazoline(0.576 g) in DMA (5 ml) was added and the mixture was stirred at ambienttemperature for 16 hours. The mixture was evaporated and the residue waspurified by column chromatography using a 9:1:0.2 mixture of methylenechloride: methanol: triethylamine as eluent. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-(1,2,3-triazole-4carboxamido)quinazoline(0.145 g); NMR Spectrum: 7.43 (m, 1H), 7.82 (d, 1H), 7.95 (m, 1H), 8.18(m, 2H). 8.43 (s, 1H), 8.58 (s, 1H), 8.88 (d, 1H), 9.89 (s, 1H), 10.55(s, 1H); Elemental Analysis: Found C, 55.6; H, 5.8; N, 21.4;C₁₇H₁₁ClFN₇O 0.8H₂O 1.1Et₃N requires C, 55.6; H, 5.7; N, 22.3%.

EXAMPLE 24

3-Pyridinecarbonyl chloride hydrochloride salt (0.107 g) was addedportionwise to a stirred mixture of6-amino4-(3-chloro-4-fluoroanilino)-7-methylaminoquinazoline (EuropeanPatent Application No. 0635507, within Example 3 thereof; 0.11 g).triethylamine (0.101 g) and DMA (1 ml). The mixture was heated to 100°C. for 3 hours. The mixture was evaporated and the residue was purifiedby column chromatography using a C18 reversed-phase silica column anddecreasingly polar mixtures of water and methanol (containing 0.2%trifluoroacetic acid) as eluent. The material so obtained was suspendedin water and basified by the addition of an aqueous ammonium hydroxidesolution. The resultant mixture was stirred at ambient temperature for 2hours. The solid was isolated, washed with water and dried. There wasthus obtained4-(3-chloro-4-fluoroanilino)-7-methylamino-6-(pyridine-3-carboxamido)quinazoline(0.061 g), m.p. >260° C.; NMR Spectrum: 2.83 (d, 3H), 6.41 (m, 1H), 6.7(s, 1H), 7.38 (m, 1H), 7.6 (m, 1H), 7.84 (m, 1H), 8.19 (m, 1H), 8.29 (s,1H), 8.42 (m, 1H), 8.48 (s, 1H), 8.79 (m, 1H), 9.24 (d, 1H), 9.5 (s,1H); Elemental Analysis: Found C, 55.1; H, 4.0; N, 18.4; C₂₁H₁₆ClFN₆O2H₂O requires C, 54.9; H, 4.4; N, 18.3%.

EXAMPLE 25

A mixture of 4-(3-chloro-4-fluoroanilino)-6-hydroxyquinazoline (0.87 g),4-fluorobenzonitrile (0.423 g), potassium carbonate (0.828 g) and DMA (5ml) was stirred and heated to 120° C. for 4 hours. The mixture wascooled to ambient temperature and partitioned between ethyl acetate andwater. The organic phase was dried (MgSO₄) and evaporated. The residuewas triturated under a mixture of methylene chloride and methanol. Therewas thus obtained4-(3-chloro-4-fluoroanilino)-6-(4-cyanophenoxy)quinazoline NMR Spectrum:7.21 (d, 2H), 7.43 (t, 1H), 7.72 (m, 1H), 7.82 (m, 1H), 7.88 (d, 2H),7.93 (d, 1H), 8.18 (m, 1H), 8.39 (d, 1H), 8.68 (s, 1H); ElementalAnalysis: Found C, 63.9; H, 3.0; N, 14.1; C₂₁H₁₂ClFN₄O 0.2H₂O requiresC, 64.0; H, 3.2; N, 14.2%.

The 4-(3-chloro-4-fluoroanilino)-6-hydroxyquinazoline used as a startingmaterial was obtained as follows:

A mixture of 6-acetoxy4-chloroquinazoline (European Patent ApplicationNo. 0566226, Example 34, Note c; 54 g), 3-chloro-4-fluoroaniline (35.6g) and isopropanol (850 ml) was stirred and heated to reflux for 90minutes and then stored at ambient temperature for 16 hours. Theprecipitate was isolated and washed in turn with isopropanol and diethylether. There was thus obtained6-acetoxy4-(3-chloro-4-fluoroanilino)quinazoline (43.7 g, 49%).

A concentrated aqueous ammonium hydroxide solution (30% weight/volume,35 ml) was added to a stirred mixture of6-acetoxy-4-(3-chloro-4-fluoroanilino)quinazoline (22 g) and methanol(200 ml) and the mixture was heated to reflux for 3 hours. The mixturewas evaporated and water (300 ml) was added to the residue. The solidwas isolated, washed in turn with water (100 ml) and ethanol (60 ml) anddried. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-hydroxyquinazoline (16.1 g, 93%); NMRSpectrum: 7.43 (t, 1H), 7.45 (m, 1H), 7.70 (d, 1H), 7.78 (d, 1H), 7.88(m, 1H), 8.24 (m, 1H), 8.5 (s, 1H), 9.6 (broad s, 1H), 10.1 (broad s,1H).

EXAMPLE 26

A mixture of 4-(3-chloro-4-fluoroanilino)-6-hydroxyquinazoline (5 g),4-fluoronitrobenzene (2.67 g), potassium carbonate (4.74 g) and DMA (50ml) was stirred and heated to 70° C. for 10 minutes. The mixture wascooled to ambient temperature and then added dropwise to a stirredslurry of ice and water. The resultant precipitate was isolated, washedin turn with water, with a small volume of methanol and with diethylether and dried. There was thus obtained4-(3-chloro-4-fluoroanilino)6-(4-nitrophenoxy)quinazoline (6.8 g); NMRSpectrum: 7.27 (d, 2H), 7.43 (t, 1H), 7.75 (m, 1H), 7.8 (m, 1H), 7.97(d, 1H), 8.18 (m, 1H), 8.29 (d, 2H), 8.42 (d, 1H), 8.69 (s, 1H);Elemental Analysis: Found C, 58.1; H, 2.8; N, 13.4; C₂₀H₁₂ClFN₄O₃requires C, 58.5; H, 2.9; N, 13.6%.

EXAMPLE 27

A mixture of 4-(3-chloro-4-fluoroanilino)-6-(4-nitrophenoxy)quinazoline(6 g), 10% palladium-on-carbon catalyst (0.6 g) and DMA (250 ml) wasstirred and heated to 60° C. under an atmosphere of hydrogen for 2hours. The mixture was filtered and the filtrate was evaporated. Theresidue was purified by column chromatography using initially methylenechloride and then increasingly polar mixtures of methylene chloride andmethanol as eluent. The product so obtained was triturated undermethanol. There was thus obtained6-(4-aminophenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline (2.3 g); NMRSpectrum: 5.0 (broad s, 2H), 6.63 (d, 2H), 6.84 (d, 2H), 7.42 (t, 1H),7.45 (m, 1H), 7.78 (d, 1H), 7.85 (m, 1H), 8.08 (d, 1H), 8.17 (m, 1H),8.57 (s, 1H), 9.75 (s, 1H); Elemental Analysis: Found C, 62.7; H, 3.8;N, 14.7; C₂₀H₁₄ClFN₄O requires C, 63.1; H, 3.7; N, 14.7%.

EXAMPLE 28

tert-Butyl nitrite (0.243 g) was added to a stirred solution of6-(4-aminophenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline (0.45 g) inDMF (25 ml) and the mixture was heated to 90° C. for 3 hours. Themixture was cooled to ambient temperature and acidified by the additionof glacial acetic acid. The mixture was evaporated and the residue waspurified by column chromatography using increasingly polar mixtures ofmethylene chloride and methanol as eluent. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-phenoxyquinazoline (0.207 g); NMRSpectrum: 7.0-7.3 (m, 5H), 7.32 (d, 1H), 7.35-7.6 (m, 3H), 7.9 (m, 1H),7.93 (d, 1H), 8.73 (s, 1H); Elemental Analysis: Found C, 62.6; H, 3.9;N, 11.5; C₂₀H₁₃ClFN₃O 1H₂O requires C, 62.6; H, 3.9; N, 11 5%.

EXAMPLE 29

4-(3-Chloro-4-fluoroanilino)-6-(4-cyanophenoxy)quinazoline (2.7 g) wasadded portionwise to a stirred mixture of lithium aluminium hydride (1Min THF, 10 ml) and diethyl ether (50 ml). The resultant mixture wasstirred at ambient temperature for 1 hour. Glacial acetic acid was addeddropwise to destroy the excess of reducing agent. The mixture waspartitioned between ethyl acetate and a dilute aqueous ammoniumhydroxide solution. The organic phase was dried (MgSO₄) and evaporated.The residue was purified by column chromatography using increasinglypolar mixtures of methylene chloride and methanol as eluent. There wasthus obtained6-(4-aminomethylphenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline (1.8g); NMR Spectrum: 3.23 (s, 2H), 3.8 (broad s, 2H), 7.18 (d, 2H), 7.43(d, 2H), 7.47 (t, 1H), 7.6 (m, 1H), 7.86 (m, 1H), 7.9 (d, 1H), 8.22 (m,1H), 8.31 (d, 1H), 8.65 (s, 1H); Elemental Analysis: Found C, 61.0; H,4.4; N, 13.3; C₂₁H₁₆ClFN₄O 1H₂O requires C, 61.1; H, 4.4; N, 13.6%.

EXAMPLE 30

Di-(2-bromoethyl)ether (0.28 g) was added to a stirred mixture of6-(4-aminomethylphenoxy)4-(3-chloro-4-fluoroanilino)quinazoline (0.5 g),potassium carbonate (0.33 g) and DMA (5 ml). The resultant mixture wasstirred and heated to 70° C. for 30 minutes. The mixture was evaporatedand the residue was purified by column chromatography using increasinglypolar mixtures of methylene chloride and methanol as eluent. There wasthus obtained4-(3-chloro-4-fluoroanilino)-6-(4-morpholinomethylphenoxy)quinazoline(0.192 g); NMR Spectrum: 2.37 (broad s, 4H), 3.49 (s, 2H), 3.62 (broads, 4H), 7.02 (d, 2H), 7.34 (d, 2H), 7.41 (t, 1H), 7.58 (m, 1H), 7.82 (m,2H), 8.2 (m, 2H), 8.62 (s, 1H), 9.79 (broad s, 1H); Elemental Analysis:Found C, 63.4; H, 5.0; N, 12.0; C₂₅H₂₂ClFN₄O₂ 0.5H₂O requires C, 63.4;H, 4.9; N, 11.8%.

EXAMPLE 31

A mixture of 6-bromomethyl-4-(3-methylanilino)quinazoline (EuropeanPatent Application No. 0566226, Example 35 thereof; 0.3 g), imidazole(0.264 g) and ethanol (4 ml) was stirred at ambient temperature for 4hours. The mixture was evaporated and the residue was purified on a C18reversed-phase silica column using decreasingly polar mixtures of waterand methanol, each containing 0.2% trifluoroacetic acid, as eluent.There was thus obtained6-(1-imidazolylmethyl)-4-(3-methylanilino)quinazoline (0.27 g), m.p.151-155° C.; NMR Spectrum: 2.37 (s, 3H), 5.66 (s, 2H), 7.07 (d, 1H),7.36 (t, 1H), 7.53 (s, 1H), 7.58 (d, 1H), 7.74 (m, 1H), 7.8 (d, 1H),7.88 (d, 1H), 7.97 (m, 1H), 8.69 (s, 1H), 8.79 (s, 1H), 9.26 (s, 1H),10.78 (broad s, 1H); Elemental Analysis: Found C, 49.1; H. 3.8; N. 12.2;C₁₉H₁₇N₅ 2CF₃CO₂H 1H₂O requires C, 49.2; H, 3.7; N, 12.5%.

EXAMPLE 32

A mixture of 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline(0.5 g), 2-chloromethylpyridine hydrochloride salt (0.282 g), potassiumcarbonate (1.5 g) and DMF (15 ml) was stirred and heated to 80° C. for 2hours. The mixture was cooled to ambient temperature and poured intowater. The precipitate was isolated and recrystallised from methanol.There was thus obtained4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(2-pyridylmethoxy)quinazoline(0.37 g); NMR Spectrum: 3.98 (s, 3H), 5.35 (s, 2H), 7.26 (s, 1H), 7.4(m, 2H), 7.64 (m, 1H), 7.8 (m, 1H), 7.9 (m, 1H), 8.01 (s, 1H), 8.15 (m,1H), 8.51 (s, 1H), 8.62 (m, 1H), 9.56 (s, 1H); Elemental Analysis: FoundC, 61.1; H, 4.0; N, 13.5; C₂₁H₁₆ClFN₄O₂ requires C, 61.4; H, 3.9; N,13.6%.

The 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline used asa starting material was obtained as follows:

6,7-Dimethoxy-3,4-dihydroquinazolin-4-one (European Patent ApplicationNo. 0566226, Example 1 thereof; 26.5 g) was added portionwise to stirredmethanesulphonic acid (175 ml). L-Methionine (22 g) was added and theresultant mixture was stirred and heated to reflux for 5 hours. Themixture was cooled to ambient temperature and poured onto a mixture (750ml) of ice and water. The mixture was neutralised by the addition of aconcentrated (40%) aqueous sodium hydroxide solution. The precipitatewas isolated, washed with water and dried. There was thus obtained6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (11.5 g).

After repetition of the previous reaction, a mixture of6-hydroxy-7-methoxy-3,4-dihydroquinazolin-4-one (14.18 g), aceticanhydride (110 ml) and pyridine (14 ml) was stirred and heated to 100°C. for 2 hours. The mixture was poured onto a mixture (200 ml) of iceand water. The precipitate was isolated, washed with water and dried.There was thus obtained 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one(13 g, 75%); NMR Spectrum: 2.3 (s, 3H), 3.8 (s, 3H), 7.3 (s, 1H), 7.8(s, 1H), 8.1 (s, 1H), 12.2 (broad s, 1H).

After repetition of the previous steps, a mixture of6-acetoxy-7-methoxy-3,4-dihydroquinazolin4-one (15 g), thionyl chloride(215 ml) and DMF (4.3 ml) was stirred and heated to 90° C. for 4 hours.The mixture was cooled to ambient temperature and the thionyl chloridewas evaporated. There was thus obtained6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride salt which wasused without further purification.

A mixture of the material so obtained, 3-chloro-4-fluoroaniline (9.33 g)and isopropanol (420 ml) was stirred and heated to 90° C. for 5 hours.The mixture was cooled to ambient temperature and the precipitate wasisolated, washed in turn with isopropanol and methanol and then dried.There was thus obtained6-acetoxy-4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolinehydrochloride salt (14 g, 56%); NMR Spectrum: 2.4 (s, 3H), 4.0 (s, 3H),7.5 (t, 1H), 7.6 (s, 1H), 7.75 (m, 1H), 8.05 (m, 1H), 8.8 (s, 1H), 8.95(s, 1H), 11.5 (broad s, 1H).

A concentrated aqueous ammonium hydroxide solution (30% weight/volume,7.25 ml) was added to a stirred mixture of the material so obtained andmethanol (520 ml). The mixture was stirred at ambient temperature for 17hours and then heated to 100° C. for 1.5 hours. The mixture was cooledand the precipitate was isolated and dried. There was thus obtained4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline (10.62 g,95%), m.p. >270° C. (decomposes); NMR Spectrum: 4.0 (s, 3H), 7.2 (s,1H), 7.4 (t, 1H), 7.8 (s, 1H), 7.85 (m, 1H), 8.2 (m, 1H), 8.5 (s, 1H),9.45 (s, 1H), 9.65 (s, 1H).

EXAMPLE 33

Using an analogous procedure to that described in Example 32,4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reactedwith 3-chloromethylpyridine, hydrochloride salt to give4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-pyridylmethoxy)quinazolinein 18% yield; NMR Spectrum: 3.93 (s, 3H), 5.28 (s, 2H), 7.16 (s, 1H),7.4 (m, 2H), 7.75 (m, 1H), 7.95 (m, 1H), 8.1 (m, 2H), 8.4 (s, 1H), 8.6(m, 1H), 8.75 (m, 1H); Elemental Analysis: Found C, 61.0; H, 3.9; N,13.5; C₂₁H₁₆ClFN₄O₂ requires C, 61.4; H, 3.9; N, 13.6%.

EXAMPLE 34

A mixture of 6-bromomethyl4-(3-methylanilino)quinazoline (0.3 g),4-mercapto-1,2,3-triazole disodium salt (0.535 g) and DMF (3 ml) wasstirred at ambient temperature for 3 hours. The mixture was evaporatedand the residue was purified by column chromatography using a C18reversed-phase silica column and a 1:1 mixture of methanol and water,each containing 0.2% trifluoroacetic acid, as eluent. There was thusobtained 4-(3-methylanilino)-6-(1,2,3-triazol-4-ylthiomethyl)quinazoline(0.22 g), m.p. 64-68° C.; NMR Spectrum: 2.38 (s, 3H), 4.36 (s, 2H), 7.15(d, 1H), 7.38 (t, 1H), 7.49 (m, 2H), 7.83 (s, 1H), 8.0 (m, 1H), 8.58 (d,1H), 8.87 (s, 1H), 11.2 (broad s, 1H); Elemental Analysis: Found C,47.5; H, 3.4; N, 16.0; C₁₈H₁₆N₆S 1.6CF₃CO₂H 0.25H₂O requires C, 47.6; H,3.4; N, 15.7%.

EXAMPLE 35

Using an analogous procedure to that described in Example 34,6-bromomethyl-4-(3-methylanilino)quinazoline was reacted with2-mercapto-1-methylimidazole sodium salt [prepared by the reaction of2-mercapto-1-methylimidazole and sodium ethoxide in ethanol] to give4-(3-methylanilino)-6-(N-methylimidazol-2-ylthiomethyl)quinazoline in65% yield, m.p. 137-139° C.; NMR Spectrum: 2.42 (s, 3H), 3.6 (s, 3H),4.48 (s, 2H), 6.97 (d, 1H), 7.13 (d, 1H), 7.39 (t, 1H), 7.55 (m, 2H),7.6 (d, 1H), 7.83 (d, 1H), 7.93 (m, 1H), 8.5 (s, 1H), 8.83 (s, 1H), 10.9(broad s, 1H); Elemental Analysis: Found C, 48.3; H, 3.6; N, 11.6;C₂₀H₁₉N₅S 2CF₃CO₂H 0.5H₂O requires C, 48.1; H, 3.5; N, 11.7%.

EXAMPLE 36

A mixture of 6-bromomethyl-4-(3-methylanilino)quinazoline (1.6 g),2-mercaptoimidazole (0.316 g) and DMF (20 ml) was stirred and heated at60° C. for 6 hours. The mixture was cooled to ambient temperature andevaporated. The residue was purified by column chromatography usingincreasingly polar mixtures of methylene chloride and methanol aseluent. There was thus obtained6-(2-imidazolylthiomethyl)-4-(3-methylanilino)quinazoline (0.43 g), m.p.217-219° C.; NMR Spectrum: 2.33 (s, 3H), 4.45 (s, 2H), 6.97 (d, 1H),7.12 (s, 2H), 7.29 (m, 1H), 7.64 (m, 2H), 7.72 (m, 2H), 8.47 (s, 1H),8.57 (s, 1H); Element Analysis: Found C, 65.8; H, 4.6; N. 19.9;C₁₉H₁₇N₅S requires C, 65.7; H, 4.9; N, 20.2%.

EXAMPLE 37

Using an analogous procedure to that described in Example 34,6-bromomethyl-4-(3-methylanilino)quinazoline was reacted with2-mercaptobenzimidazole sodium salt to give6-(2-benzimidazolylthiomethyl)4-(3-methylanilino)quinazoline in 59%yield, m.p. 123-129° C.; NMR Spectrum: 2.34 (s, 3H), 4.77 (s, 2H), 6.96(d, 1H), 7.13 (m, 2H), 7.28 (t, 1H), 7.46 (broad s, 2H), 7.68 (m, 3H),7.96 (m, 1H), 8.57 (s, 1H), 8.65 (d, 1H), 9.79 (broad s, 1H); ElementalAnalysis: Found C, 64.9; H, 5.3; N, 15.9; C₂₃H₁₉N₅S 1.6H₂O 0.1CH₃OHrequires C, 64.5; H, 5.3; N, 16.3%.

EXAMPLE 38

Using an analogous procedure to that described in Example 5,6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazolinedihydrochloride salt was reacted with di-isopropyl 2-thienylboronate togive 4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-(2-thienyl)quinazolinein 70% yield, m.p. 205-206° C.; NMR Spectrum: 2.3 (s, 3H), 5.2 (s, 2H),7.0 (d, 1H), 7.2 (m, 1H), 7.35 (m, 1H), 7.5 (m, 3H), 7.6 (m, 1H), 7.7(m, 1H), 7.75 (d, 1H), 7.85 (m, 1H), 8.1 (m, 1H), 8.48 (s, 1H), 8.55 (m,1H), 8.75 (d, 1H), 9.8 (broad s, 1H); Elemental Analysis: Found C, 70.8;H, 4.7; N, 13.0; C₂₅H₂₀N₄OS requires C, 70.7; H, 4.75, N, 13.2%.

The 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazolinedihydrochloride salt used as a starting material was obtained asfollows:

Sodium hydride (60% dispersion in mineral oil, 1.24 g) was added to asolution of 2-pyridylmethanol (2.49 ml) in NMP (100 ml) and the mixturewas stirred at ambient temperature for 15 minutes.2-Fluoro-5-nitrotoluene (4 g) was added and the mixture was heated to140° C. for 2.5 hours. The mixture was cooled to ambient temperature,poured into water (300 ml) and stirred for 30 minutes. The precipitatewas isolated, washed with water and dried. The material so obtained waspurified by column chromatography using increasingly polar mixtures ofmethylene chloride and methanol as eluent. There was thus obtained5-nitro-2-tolyl 2-pyridylmethyl ether (1.61 g, 26%); NMR Spectrum: 2.32(s, 3H), 5.35 (s, 2H), 7.21 (d, 1H), 7.35 (m, 1H), 7.55 (d, 1H), 7.85(m, 1H), 8.09 (m, 1H), 8.1 (s, 1H), 8.6 (m, 1H).

A mixture of 5-nitro-2-tolyl 2-pyridylmethyl ether (2 g), iron powder (1g), concentrated hydrochloric acid (1 ml), water (2 ml) and ethanol (50ml) was stirred and heated to reflux for 4 hours. The mixture wasallowed to cool to ambient temperature, basified by the addition of 2Maqueous sodium hydroxide solution and extracted with methylene chloride.The organic phase was dried (MgSO₄) and evaporated. There was thusobtained 5-amino-2-tolyl 2-pyridylmethyl ether in 97% yield; NMRSpectrum: 2.09 (s, 3H), 4.61 (s, 2H), 5.0 (s, 2H), 6.32 (m, 1H), 6.42(d, 1H), 6.67 (d, 1H), 7.31 (m, 1H), 7.50 (d, 1H), 7.81 (m, 1H), 8.54(m, 1H).

Using an analogous procedure to that described in the third paragraph ofthe portion of Example 1 which is concerned with the preparation ofstarting materials, except that the product was recrystallised from amixture of methanol and ethanol, 6-bromo-4-chloroquinazoline was reactedwith 5-amino-2-tolyl 2-pyridylmethyl ether to give6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazolinedihydrochloride salt in 68% yield, m.p. 232-234° C.; NMR Spectrum: 2.3(s, 3H), 5.35 (s, 2H), 7.13 (m, 1H), 7.52 (m, 3H), 7.63 (d, 1H), 7.9 (d,1H), 8.08 (m, 1H), 8.25 (m, 1H), 8.7 (m, 1H), 8.92 (s, 1H), 9.17 (d,1H), 11.62 (d, 1H); Elemental Analysis: Found C, 48.4; H, 4.2; N, 10.6;C₂₁H₁₇BrN₄O 2HCl 1.5H₂O requires C, 48.4; H, 4.25; N, 10.7%.

EXAMPLE 39

Using an analogous procedure to that described in Example 5,6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazolinedihydrochloride salt was reacted with di-isopropyl 3-furylboronate togive 6-(3-furyl)-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-quinazoline in55% yield, m.p. 206-208° C.; NMR Spectrum: 2.32 (s, 3H), 5.22 (s, 2H),7.05 (d, 1H), 7.15 (d, 1H), 7.36 (m, 1H), 7.55 (m, 3H), 7.75 (d, 1H),7.87 (m, 2H), 8.1 (m, 2H), 8.33 (d, 1H), 8.48 (s, 1H), 8.6 (m, 1H), 8.69(d, 1H), 9.62 (s, 1H); Elemental Analysis: Found C, 73.2; H, 4.9; N,13.6; C₂₅H₂₀N₄O₂ requires C, 73.5; H, 4.9; N, 13.7%.

The di-isopropyl 3-furylboronate used as a starting material wasobtained as follows:

n-Butyllithium (1.6M in hexane, 1 ml) was added dropwise to a stirredmixture of 3-bromofuran (0.21 g), tri-isopropyl borate (0.4 ml) and THF(5 ml) which had been cooled to −78° C. The mixture was stirred andallowed to warm to ambient temperature. The mixture was evaporated togive the required starting material which was used without furtherpurification.

EXAMPLE 40

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 LactosePh.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0Polyvinylpyrrolidone 2.25 Magnesium stearate 3.0 (c) Tablet IIImg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0 (d)Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium stearate1.5 (e) Injection I (50 mg/ml) Compound X 5.0% w/v 0.1M Sodium hydroxidesolution 15.0% w/v 0.1M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f)Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g)Injection III (1 mg/ml, buffered to pH6) Compound X 0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 4003.5% w/v Water for injection to 100%

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

What we claim is:
 1. A compound of the formula I

wherein X¹ is a group of the formula CO, CH(OR²), C(R²)═C(R²), C≡C,CH(CN), O, S, SO, SO₂, N(R²), CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂,OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂, C(R²)₂O, C(R²)₂S or C(R²)₂N(R²), and eachR² is independently hydrogen or (1-4C)alkyl; wherein Q¹ is naphthyl or a5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heterocyclic moiety isa single ring or is fused to a benzo ring, and Q¹ optionally bears up to3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy,trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,(1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl,di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl,piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl,piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl,halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy,amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy,di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy,piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy,piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy,(1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy,(1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino,hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino,amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl; and wherein Q²is phenyl or a 9- or10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogenheteroatoms and optionally containing a further heteroatom selected fromoxygen, nitrogen and sulphur, and Q² optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, or Q² is a group of the formula II

wherein X² is a group of the formula CO, C(R³)₂, CH(OR³), C(R³)₂—C(R³)₂,C(R³)═C(R³), C≡C, CH(CN), O, S, SO, SO₂, N(R³), CON(R³), SO₂N(R³),N(R³)CO, N(R³)SO₂, OC(R³)₂, SC(R³)₂, C(R³)₂O or C(R³)₂S wherein each R³is independently hydrogen or (1-4C)alkyl, Q³ is phenyl or naphthyl or a5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heteroaryl moiety is asingle ring or is fused to a benzo ring, and wherein said phenyl ornaphthyl group or heteroaryl moiety optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-[(1-4C)alkyl]carbamoyl, n is 1, 2 or 3 and each R⁴ isindependently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino or (2-4C)alkanoylamino; or apharmaceutically-acceptable salt thereof.
 2. The compound of the formulaI as claimed in claim 1 wherein X¹ is a group of the formula CO,CH(OR²), C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²), CON(R²),SO₂N(R²), N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂, C(R²)₂O,C(R²)₂S or C(R²)₂N(R²), and each R² is independently hydrogen or(1-4C)alkyl; wherein Q¹ is a 5- or 6-membered heteroaryl moietycontaining up to 3 heteroatoms selected from oxygen, nitrogen andsulphur, which heterocyclic moiety is a single ring or is fused to abenzo ring, and Q¹ optionally bears up to 3 substituents selected fromhalogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano,nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl,N′N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy,pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy,morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy,(1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy,halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino,(1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino,(1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl; and wherein Q² is phenyl which optionallybears up to 3 substituents selected from halogeno, trifluoromethyl,cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl; or a pharmaceutically-acceptable saltthereof.
 3. The compound of the formula I as claimed in claim 1 whereinX¹ is a group of the formula NH, NHCO, NHSO₂, OCH₂, SCH₂, NHCH₂, CH₂O orCH₂S; Q¹ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-oxazolyl, 4-oxazolyl, 5-isoxazolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-isothiazolyl or1,2,3-triazol-4-yl which optionally bears a substituent selected frommethyl, aminomethyl, 2-aminoethyl, methylaminomethyl,2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl,pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl,2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl; m is 1and R¹ is hydrogen or methoxy; and Q² is phenyl which optionally bears1, 2 or 3 substituents selected from fluoro, chloro, bromo,trifluoromethyl, cyano, methyl and methoxy, or Q² is a group of theformula II

wherein X² is a group of the formula CO or OCH₂, Q³ is phenyl or2-pyridyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro, bromo, methyl and methoxy, n is 1 and R⁴ is hydrogen,fluoro, chloro, bromo or methyl; or a pharmaceutically-acceptableacid-addition salt thereof.
 4. The compound of the formula as claimed inclaim 1 wherein X¹ is a group of the formula NHCO, OCH₂ OR NHCH₂; Q₁ is2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-oxazolylor 4-imidazolyl which optionally bears a substituent selected fromaminomethyl, morpholinomethyl and 2-morpholinoethyl; m is 1 and R¹ ishydrogen or methoxy; and Q² is phenyl which optionally bears 1 and 2substituents selected from fluoro, chloro, bromo and methyl; or apharmaceutically-acceptable acid-addition salt thereof.
 5. The compound4-(3chloro-4-fluoroanilino)-7-methoxy-6-(3-pyridylmethoxy)quinazoline ora pharmaceutically-acceptable acid-addition salt thereof.
 6. A compoundof the formula I

wherein X¹ is a group of the formula CO, CH(OR²), C(R²)═C(R²), C≡C,CH(CN), O, S, SO, SO₂, N(R²), CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂,OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂, C(R²)₂S or C(R²)₂N(R²), and each R² isindependently hydrogen or (1-4C)alkyl; wherein Q¹ is phenyl, naphthyl ora 5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heterocyclic moiety isa single ring or is fused to a benzo ring, and Q¹ optionally bears up to3 substituents selected from halogeno, hydroxy, amino, trifluoromethoxy,trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,(1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino,N-(1-4C)alkylcarbarmoyl, N,N-di-[(1-4C)alkyl]carbamoyl,amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl,di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl,piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl,piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl,halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy,amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy,di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy,piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy,piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy,(1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy,(1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino,hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino,amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl)amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl; and wherein Q² is phenyl or a 9- or10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogenheteroatoms and optionally containing a further heteroatom selected fromoxygen, nitrogen and sulphur, and Q² optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, or Q² is a group of the formula II

wherein X²is a group of the formula CO, C(R³)₂, CH(OR³), C(R³)₂—C(R³)₂,C(R³)═C(R³), C≡C, CH(CN), O, S, SO, SO₂, N(R³), CON(R³), SO₂N(R³),N(R³)CO, N(R³)SO₂, OC(R³)₂, SC(R³)₂, C(R³)₂O or C(R³)₂S wherein each R³is independently hydrogen or (1-4C)alkyl, Q³ is phenyl or naphthyl or a5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heteroaryl moiety is asingle ring or is fused to a benzo ring, and wherein said phenyl ornaphthyl group or heteroaryl moiety optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-[(1-4C)alkyl]carbamoyl, n is 1, 2 or 3 and each R⁴ isindependently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino or (2-4C)alkanoylamino; or apharmaceutically-acceptable salt thereof; provided that, when Q¹ isoptionally-substituted phenyl, X¹ is not N(R²)CO, N(R²)SO₂, OC(R²)₂,N(R²)C(R²)₂, C(R²)₂S or C(R²)₂N(R²).
 7. The compound of the formula I asclaimed in claim 6 wherein X¹ is a group of the formula O; Q¹ is phenylwhich optionally bears 1 or 2 substituents selected from fluoro, chloro,bromo, amino, cyano, nitro, aminomethyl, methylaminomethyl,dimethylaminomethyl, diethylaminomethyl, pyrrolidin-1-ylmethyl,piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-methylpiperazin-1-ylmethyl; m is 1 and R¹ is hydrogen or methoxy; andQ² is phenyl which optionally bears 1, 2 or 3 substituents selected fromfluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy, or upof the formula II

wherein X² is a group of the formula OCH₂, Q³ is 2-pyridyl, n is 1 andR⁴ is hydrogen, fluoro, chloro or methyl; or apharmaceutically-acceptable acid-addition salt thereof.
 8. The compoundof the formula I as claimed in claim 6 wherein X¹ is a group of theformula O; Q¹ is phenyl which optionally bears 1 or 2 substituentsselected from amino, aminomethyl, diethylaminomethyl, pyrrolidin-l-ylmethyl, piperidinomethyl and morpholinomethyl; m is 1 and R¹ ishydrogen; and Q² is phenyl which optionally bears 1 or 2 substituentsselected from fluoro, chloro and methyl; or apharmaceutically-acceptable acid-addition salt thereof.
 9. A compound ofthe formula I

wherein X¹ is a direct link or a group of the formula CO, CH(OR²),C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²), CON(R²), SO₂N(R²),N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂, C(R²)₂O, C(R²)₂S orC(R²)₂N(R²), and each R² is independently hydrogen or (1-4C)alkyl;wherein Q¹ is naphthyl, a 5-membered heteroaryl moiety containing onenitrogen heteroatom, a 5-membered heteroaryl moiety containing 2 or 3heteroatoms selected from oxygen, nitrogen and sulphur, or a 6-memberedheteroaryl moiety containing up to 3 heteroatoms selected from oxygen,nitrogen and sulphur, which heterocyclic moiety is a single ring or isfused to a benzo ring, and Q¹ optionally bears up to 3 substituentsselected from halogeno, hydroxy, amino, trifluoromethoxy,trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,(1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl,di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl,piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl,piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl,halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy,amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy,di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy,piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy,piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy,(1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy,(1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino,hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino,amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN′N-di-[(1-4C)alkyl]carbamoyl; and wherein Q² is phenyl or a 9- or10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogenheteroatoms and optionally containing a further heteroatom selected fromoxygen, nitrogen and sulphur, and Q² optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, or Q² is a group of the formula II

wherein X²is a group of the formula CO, C(R³)₂, CH(OR³), C(R³)₂—C(R³)₂,C(R³)═C(R³), C≡C, CH(CN), O, S, SO, SO₂, N(R³), CON(R³), SO₂N(R³),N(R³)CO, N(R³)SO₂, OC(R³)₂, SC(R³)₂, CR(³)₂ O or C(R³)₂S wherein each R³is independently hydrogen or (1-4C)alkyl, Q³ is phenyl or naphthyl or a5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heteroaryl moiety is asingle ring or is fused to a benzo ring, and wherein said phenyl ornaphthyl group or heteroaryl moiety optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-[(1-4C)alkyl]carbamoyl, n is 1, 2 or 3 and each R⁴ isindependently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino or (2-4C)alkanoylamino; or apharmaceutically-acceptable salt thereof; provided that, when X¹ is adirect link, Q¹ is not a 5- or 9-membered nitrogen-linked heteroarylmoiety containing up to 3 nitrogen heteroatoms.
 10. The compound of theformula I as claimed in claim 9 wherein X¹ is a direct link or a groupof the formula CO, CH(OR²), C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂,N(R²), CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂,N(R²)C(R²)₂, C(R²)₂O, C(R²)₂S or C(R²)₂N(R²), and each R² isindependently hydrogen or (1-4C)alkyl; wherein Q¹ is a 5-memberedheteroaryl moiety containing one nitrogen heteroatom, a 5-memberedheteroaryl moiety containing 2 or 3 heteroatoms selected from oxygen,nitrogen and sulphur, or a 6-membered heteroaryl moiety containing up to3 heteroatoms selected from oxygen, nitrogen and sulphur, whichheterocyclic moiety is a single ring or is fused to a benzo ring, and Q¹optionally bears up to 3 substituents selected from halogeno, hydroxy,amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy,carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy,pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy,morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy,(1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy,halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino,(1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino,(1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)allyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl; and wherein Q² is phenyl which optionallybears up to 3 substituents selected from halogeno, trifluoromethyl,cyano, hydroxy, amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl; or a pharmaceutically-acceptable saltthereof; provided that, when X¹ is a direct link, Q¹ is not a 5- or9-membered nitrogen-linked heteroaryl moiety containing up to 3 nitrogenheteroatoms.
 11. The compound of the formula I as claimed in claim 9wherein X¹ is a direct link or a group of the formula NH, NHCO, NHSO₂,OCH₂, SCH₂, NHCH₂, CH₂O or CH₂S; Q¹ is 2-pyridyl, 3-pyridyl, 4-pyridyl,2-oxazolyl, 4-oxazolyl, 5-isoxazolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, 2-thiazolyl, 4-thiazolyl, 5-isothiazolyl or1,2,3-triazol-4-yl which optionally bears a substituent selected frommethyl, aminomethyl, 2-aminoethyl, methylaminomethyl,2-methylaminoethyl, dimethylaminomethyl, 2-dimethylaminoethyl,pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, piperidinomethyl,2-piperidinoethyl, morpholinomethyl, 2-morpholinoethyl,piperazin-1-ylmethyl, 2-piperazin-1-ylethyl,4-methylpiperazin-1-ylmethyl and 2-(4-methylpiperazin-1-yl)ethyl; m is 1and R¹ is hydrogen or methoxy; and Q² is phenyl which optionally bears1, 2 or 3 substituents selected from fluoro, chloro, bromo,trifluoromethyl, cyano, methyl and methoxy, or Q² is a group of theformula II

wherein X² is a group of the formula CO or OCH₂, Q³is phenyl or2-pyridyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro, bromo, methyl and methoxy, n is 1 and R⁴ is hydrogen,fluoro, chloro, bromo or methyl; or a pharmaceutically-acceptableacid-addition salt thereof.
 12. A compound of the formula I

wherein X¹ is a direct link or a group of the formula CO, CH(OR²),C(R¹)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²), CON(R²), SO₂N(R²),N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂, C(R²)₂S orC(R²)₂N(R²), and each R² is independently hydrogen or (1-4C)alkyl;wherein Q¹ is phenyl, naphthyl, a 5-membered heteroaryl moietycontaining one nitrogen heteroatom, a 5-membered heteroaryl moietycontaining 2 or 3 heteroatoms selected from oxygen, nitrogen andsulphur, or a 6-membered heteroaryl moiety containing up to 3heteroatoms selected from oxygen, nitrogen and sulphur, whichheterocyclic moiety is a single ring or is fused to a benzo ring, and Q¹optionally bears up to 3 substituents selected from halogeno, hydroxy,amino, trifluoromethoxy, trifluoromethyl, cyano, nitro, carboxy,carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,(2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy,pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy,morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy,(1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy,halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino,(1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino,(1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl, and wherein Q² is phenyl or a 9- or10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogenheteroatoms and optionally containing a further heteroatom selected fromoxygen, nitrogen and sulphur, and Q² optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-(1-4C)alkylcarbamoyl, or Q² is a group of the formula II

wherein X² is a group of the formula CO, C(R³)₂, CH(OR³), C(R³)₂—C(R³)₂,C(R³)═C(R³), C≡C, CH(CN), O, S, SO, SO₂, N(R³), CON(R³), SO₂N(R³),N(R³)CO, N(R³)SO₂, OC(R³)₂, SC(R³)₂, C(R³)₂O or C(R³)₂S wherein each R³is independently hydrogen or (1-4C)alkyl, Q³ is phenyl or naphthyl or a5- or 6-membered heteroaryl moiety containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur, which heteroaryl moiety is asingle ring or is fused to a benzo ring, and wherein said phenyl ornaphthyl group or heteroaryl moiety optionally bears up to 3substituents selected from halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl andN,N-di-[(1-4C)alkyl]carbamoyl, n is 1, 2 or 3 and each R⁴ isindependently hydrogen, halogeno, trifluoromethyl, cyano, hydroxy,amino, nitro, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino or (2-4C)alkanoylamino; or apharmaceutically-acceptable salt thereof; provided that, when Q¹ isoptionally-substituted phenyl, X¹ is not N(R²)CO, N(R²)SO₂, OC(R²)₂,N(R²)C(R²)₂, C(R²)₂S or C(R²)₂N(R²); and when X¹ is a direct link, Q¹ isnot a 5- or 9-membered nitrogen-linked heteroaryl moiety containing upto 3 nitrogen heteroatoms.
 13. The quinazoline of the formula I asclaimed in claim 9 wherein X¹ is a direct link or a group of the formulaO; Q¹ is phenyl which optionally bears 1 or 2 subtituents selected fromamino, amniomethyl, diethylaminomethyl, pyrrolidin-1-ylmethyl,piperidinomethyl and morpholinomethyl; m is 1 and R¹ is hydrogen; and Q²is phenyl which optionally bears 1 or 2 substituents selected fromfluoro, chloro and methyl; or a pharmaceutically-acceptableacid-addition salt thereof.
 14. The quinazoline derivative of theformula I as claimed in claim 9 wherein X¹ is a direct link or a groupof the formula NHCO, OCH₂ or NHCH₂; Q¹ is 2-pyridyl, 3-pyridyl,4-oxazolyl, 5-isoxazolyl or 4-imidazolyl which optionally bears asubstituent selected from aminomethyl, morpholinomethyl and2-morpholinoethyl; m is 1 and R¹ is hydrogen or methoxy; and Q² isphenyl which optionally bears 1 or 2 substituents selected from fluoro,chloro, bromo and methyl; or a pharmaceutically-acceptable acid-additionsalt thereof.
 15. The compound of the formula I as claimed in claim 13wherein X¹ is a direct link or a group of the formula O; Q¹ is phenylwhich optionally bears 1 or 2 substituents selected from fluoro, chloro,bromo, amino, cyano, nitro, aminomethyl, methylaminomethyl,dimethylaminomethyl, diethylaminomethyl, pyrrolidin-1-ylmethyl,piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-methylpiperazin-1-ylmethyl; m is 1 and R¹ is hydrogen or methoxy; andQ² is phenyl which optionally bears 1, 2 or 3 substituents selected fromfluoro, chloro, bromo, trifluoromethyl, cyano, methyl and methoxy, or Q²is a group of the formula II

wherein X² is a group of the formula OCH₂, Q³ is 2-pyridyl, n is 1 andR⁴ is hydrogen, fluoro, chloro or methyl; or apharmaceutically-acceptable acid-addition salt thereof.
 16. A compoundof the formula I

wherein X¹ is a direct link or a group of the formula CO, C(R²)₂,CH(OR²), C(R²)₂—C(R²)₂, C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²),CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂,C(R²)₂O, C(R²)₂S or C(R²)₂N(R²), and each R² is independently hydrogenor (1-4C)alkyl; wherein Q¹ is naphthyl or a 5- or 6-membered heteroarylmoiety containing up to 3 heteroatoms selected from oxygen, nitrogen andsulphur, which heterocyclic moiety is a single ring or is fused to abenzo ring, and Q¹ optionally bears up to 3 substituents selected fromhalogeno, hydroxy, amino, trifluoromethoxy, trifluoromethyl, cyano,nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy, (1-3C)alkylenedioxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, pyrrolidin-1-yl, piperidino,morpholino, piperazin-1-yl, 4-(1-4C)alkylpiperazin-1-yl,(2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl,N,N-di-[(1-4C)alkyl]carbamoyl, amino-(1-4C)alkyl,(1-4C)alkylamino-(1-4C)alkyl, di-[(1-4C)alkyl]amino-(1-4C)alkyl,pyrrolidin-1-yl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl,4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, halogeno-(2-4C)alkoxy,hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy, amino-(2-4C)alkoxy,(1-4C)alkylamino-(2-4C)alkoxy, di-[(1-4C)alkyl]amino-(2-4C)alkoxy,pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy,morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, (1-4C)alkylthio-(2-4C)alkoxy,(1-4C)alkylsulphinyl-(2-4C)alkoxy, (1-4C)alkylsulphonyl-(2-4C)alkoxy,halogeno-(2-4C)alkylamino, hydroxy-(2-4C)alkylamino,(1-4C)alkoxy-(2-4C)alkylamino, amino-(2-4C)alkylamino,(1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl; and wherein Q² is a 9- or 10-memberedbicyclic heterocyclic moiety containing 1 or 2 nitrogen heteroatoms andoptionally containing a further heteroatom selected from oxygen,nitrogen and sulphur, and Q² optionally bears up to 3 substituentsselected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl; or apharmaceutically-acceptable salt thereof; provided that, when X¹ is adirect link, Q¹ is not a 5- or 9-membered nitrogen-linked heteroarylmoiety containing up to 3 nitrogen heteroatoms.
 17. A compound of theformula I

wherein X¹ is a direct link or a group of the formula CO, C(R²)₂,CH(OR²), C(R²)₂—C(R²)₂, C(R²)═C(R²), C≡C, CH(CN), O, S, SO, SO₂, N(R²),CON(R²), SO₂N(R²), N(R²)CO, N(R²)SO₂, OC(R²)₂, SC(R²)₂, N(R²)C(R²)₂,C(R²)₂S or C(R²)₂N(R²), and each R² is independently hydrogen or(1-4C)alkyl; wherein Q¹ is phenyl, naphthyl or a 5- or 6-memberedheteroaryl moiety containing up to 3 heteroatoms selected from oxygen,nitrogen and sulphur, which heterocyclic moiety is a single ring or isfused to a benzo ring, and Q¹ optionally bears up to 3 substituentsselected from halogeno, hydroxy, amino, trifluoromethoxy,trifluoromethyl, cyano, nitro, carboxy, carbamoyl, (1-4C)alkoxycarbonyl,(1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkynyloxy,(1-3C)alkylenedioxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino,pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl,4-(1-4C)alkylpiperazin-1-yl, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl,amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl,di-[(1-4C)alkyl]amino-(1-4C)alkyl, pyrrolidin-1-yl-(1-4C)alkyl,piperidino-(1-4C)alkyl, morpholino-(1-4C)alkyl,piperazin-1-yl-(1-4C)alkyl, 4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl,halogeno-(2-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-4C)alkoxy-(2-4C)alkoxy,amino-(2-4C)alkoxy, (1-4C)alkylamino-(2-4C)alkoxy,di-[(1-4C)alkyl]amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy,piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy,piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy,(1-4C)alkylthio-(2-4C)alkoxy, (1-4C)alkylsulphinyl-(2-4C)alkoxy,(1-4C)alkylsulphonyl-(2-4C)alkoxy, halogeno-(2-4C)alkylamino,hydroxy-(2-4C)alkylamino, (1-4C)alkoxy-(2-4C)alkylamino,amino-(2-4C)alkylamino, (1-4C)alkylamino-(2-4C)alkylamino,di-[(1-4C)alkyl]amino-(2-4C)alkylamino,pyrrolidin-1-yl-(2-4C)alkylamino, piperidino-(2-4C)alkylamino,morpholino-(2-4C)alkylamino, piperazin-1-yl-(2-4C)alkylamino,4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkylamino,N-(1-4C)alkyl-halogeno-(2-4C)alkylamino,N-(1-4C)alkyl-hydroxy-(2-4C)alkylamino,N-(1-4C)alkyl-(1-4C)alkoxy-(2-4C)alkylamino,halogeno-(2-4C)alkanoylamino, hydroxy-(2-4C)alkanoylamino,(1-4C)alkoxy-(2-4C)alkanoylamino, (3-4C)alkenoylamino,(3-4C)alkynoylamino, amino-(2-4C)alkanoylamino,(1-4C)alkylamino-(2-4C)alkanoylamino,di-[(1-4C)alkyl]amino-(2-4C)alkanoylamino,pyrrolidin-1-yl-(2-4C)alkanoylamino, piperidino-(2-4C)alkanoylamino,morpholino-(2-4C)alkanoylamino, piperazin-1-yl-(2-4C)alkanoylamino and4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkanoylamino, and wherein any of theabove-mentioned substituents comprising a CH₂ (methylene) group which isnot attached to a halogeno, SO or SO₂ group or to a N, O or S atomoptionally bears on said CH₂ group a substituent selected from hydroxy,amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; whereinm is 1 or 2 and each R¹ is independently hydrogen, halogeno,trifluoromethyl, hydroxy, amino, nitro, cyano, carboxy, carbamoyl,(1-4C)alkoxycarbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino,di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino, N-(1-4C)alkylcarbamoyl orN,N-di-[(1-4C)alkyl]carbamoyl; and wherein Q²is a 9- or 10-memberedbicyclic heterocyclic moiety containing 1 or 2 nitrogen heteroatoms andoptionally containing a further heteroatom selected from oxygen,nitrogen and sulphur, and Q² optionally bears up to 3 substituentsselected from halogeno, trifluoromethyl, cyano, hydroxy, amino, nitro,carboxy, carbamoyl, (1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)alkylamino, di-[(1-4C)alkyl]amino, (2-4C)alkanoylamino,N-(1-4C)alkylcarbamoyl and N,N-di-(1-4C)alkylcarbamoyl; or apharmaceutically-acceptable salt thereof; provided that, when Q¹ isoptionally-substituted phenyl, X¹ is not N(R²)CO, N(R²)SO₂, OC(R²)₂,N(R²)C(R²)₂, C(R²)₂S or C(R²)₂N(R²); and when X¹ is a direct link, Q¹ isnot a 5- or 9-membered nitrogen-linked heteroaryl moiety containing upto 3 nitrogen heteroatoms.
 18. A compound selected from:4-(3-methylanilino)-6-phenylquinazoline;6-(4-aminomethylphenyl)-4-(3-chloro-4-fluoroanilino)quinazoline,6-(4-aminophoxy)-4-(3-chloro-4-fluoroanilino)quinazoline,6-(4-aminomethylphenoxy)-4-(3-chloro-4-fluoroanilino)quinazoline or4-(3-chloro-4-fluoroanilino)-6-(4-morpholinomethylphenoxy)quinazoline;or a pharmaceutically-acceptable acid-addition salt thereof.
 19. Apharmaceutical composition which comprises a compound of the formula I,or a pharmaceutically-acceptable salt thereof, as claimed in any one ofclaims 1, 9 and 16 in association with apharmaceutically-acceptablediluent or carrier.
 20. A method forproducing an anti-profilerative effect in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a quinazoline derivative of the formula I,or a pharmaceutically-acceptable salt thereof, as claimed in any one ofclaims 1, 9 and 16.